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bioRxiv2016

The risk of sustained sexual transmission of Zika is underestimated

Pathogens can follow more than one transmission route during outbreaks - from needle sharing plus sexual transmission of HIV to small droplet aerosol plus fomite transmission of influenza. Thus, controlling an infectious disease outbreak often requires characterizing the risk associated with multiple mechanisms of transmission. For example, during the Ebola virus outbreak in West Africa, weighing the relative importance of funeral versus health care worker transmission was essential to stopping disease spread [1]. Strategic policy decisions regarding interventions must rely on accurately characterizing risks associated with multiple transmission routes. The ongoing Zika virus outbreak challenges our conventional methodologies for translating case-counts into route-specific transmission risk. Critically, most approaches will fail to accurately estimate the risk of seeing sustained sexual transmission of a pathogen that is primarily vectored by a mosquito - ...

epidemiology↗

bioRxiv2016

Cannabis use and risk of schizophrenia:a Mendelian randomization study

Cannabis use is observationally associated with an increased risk of schizophrenia, however whether the relationship is causal is not known. To determine the nature of the association between cannabis use on risk of schizophrenia using Mendelian randomization (MR) analysis, we used ten genetic variants previously identified to associate with cannabis use in 32,330 individuals. Genetic variants were used in a MR analyses of the association of genetically determined cannabis on risk of schizophrenia in 34,241 cases and 45,604 controls from predominantly European descent. Estimates from MR were compared to a metaanalysis of observational studies reporting effect estimates for ever use of cannabis and risk of schizophrenia or related disorders. Genetically determined use of cannabis was associated with increased risk of schizophrenia (OR of schizophrenia for users vs. non-users of cannabis: 1.37; 95%CI, 1.09 to 1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.50 (95% CI, 1.10 to 2.00; P-value for heterogeneity = 0.88). The genetic instrument did not show evidence of pleiotropy on MR-Egger (Egger test, P-value=0.292) nor on multivariable MR accounting for tobacco exposure (OR of schizophrenia for users vs. nonusers of cannabis, adjusted for ever vs. never smoker: 1.41; 95% CI, 1.09-1.83). Furthermore, the causal estimate remained robust to sensitivity analyses. These findings strongly support a causal association between genetically determined use of cannabis and risk of schizophrenia. Such robust evidence may inform public health message about the risks of cannabis use, especially regarding its potential mental health consequences.

epidemiology↗

bioRxiv2016

Detecting telomere elongation in longitudinal datasets: Analysis of a proposal by Simons, Stulp and Nakagawa

Telomere shortening has emerged as an important biomarker of aging. Longitudinal studies consistently find that, although telomere length shortens over time on average, there is a subset of individuals for whom telomere length is observed to increase. This apparent lengthening could either be a genuine biological phenomenon, or simply due to measurement and sampling error. Simons, Stulp and Nakagawa [Biogerontology 15: 99-103, 2014] recently proposed a statistical test for detecting when the amount of apparent lengthening in a dataset exceeds that which should be expected due to error, and thus indicating that genuine elongation may be operative in some individuals. The test is however based on a restrictive assumption, namely that each individuals true rate of telomere change is constant over time. It is not currently known whether this assumption is true. Here we show, using simulated datasets, that with perfect measurement and large sample size, the test has high power to detect true lengthening as long as the true rate of shortening is either constant, or moderately stable, over time. If the true rate of lengthening varies randomly from year to year, the test systematically returns type-II errors. We also consider the impact of measurement error. Using estimates of the magnitude of annual attrition and of measurement error derived from the human telomere literature, we show that power of the test is likely to be low in several empirically-realistic scenarios, even in large samples. Thus, whilst a significant result of the proposed test is likely to indicate that true lengthening is present in a data set, type-II errors are a likely outcome, either if measurement error is substantial, and/or the true rate of attrition varies substantially over time within individuals.

epidemiology↗

bioRxiv2017

The Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression

BackgroundLow and deficient levels of vitamin A are common in low and middle income countries where tuberculosis burden is high. We assessed the impact of baseline levels of vitamins A and carotenoids on TB disease risk.\n\nMethods and FindingsWe conducted a case-control study nested within a longitudinal cohort of household contacts of pulmonary TB cases in Lima, Peru. We screened all contacts for TB disease at 2, 6, and 12 months after enrollment. We defined cases as HIV-negative household contacts with blood samples who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected 4 controls from among contacts who did not develop TB disease, matching on gender and year of age. We used conditional logistic regression to estimate odds ratios (ORs) for incident TB disease by vitamin A and carotenoids levels, controlling for other nutritional and socioeconomic factors.\n\nAmong 6751 HIV-negative household contacts with baseline blood samples, 192 developed secondary TB disease during follow-up. We analyzed 180 cases with viable samples and 709 matched controls. After controlling for possible confounders, we found that baseline vitamin A deficiency was associated with a 10-fold increase in risk of TB disease among household contacts (aOR 10.42; 95% CI 4.01-27.05; p < 0.001). This association was dose-dependent with stepwise increases in TB disease risk with each decreasing quartile of vitamin A level. Carotenoid levels were also inversely associated with TB risk among adolescents.\n\nOur study is limited by the one year duration of follow up and by the relatively few blood samples available from household contacts under ten years of age.\n\nConclusionsVitamin A deficiency strongly predicted risk of incident TB disease among household contacts of TB patients. Vitamin A supplementation among individuals at high risk of TB may provide an effective means of preventing TB disease.

epidemiology↗

bioRxiv2016

Surveillance to Establish Elimination of Transmission and Freedom from Dog-mediated Rabies

BackgroundWith a global target set for zero human deaths from dog-mediated rabies by 2030 and some regional programmes close to eliminating canine rabies, there is an urgent need for enhanced surveillance strategies suitable for declaring freedom from disease and elimination of transmission with known confidence.\n\nMethodsUsing exhaustive contact tracing across settings in Tanzania we generated detailed data on rabies incidence, rabid dog biting behaviour and health-seeking behaviour of bite victims. Using these data we compared case detection of sampling-based and enhanced surveillance methodologies and investigated elimination verification procedures.\n\nFindingsWe demonstrate that patients presenting to clinics with bite injuries are sensitive sentinels for identifying dog rabies cases. Triage of patients based on bite history criteria and investigation of suspicious incidents can confirm >10% of dog rabies cases and is an affordable approach that will enable validation of disease freedom following two years without case detection. Approaches based on sampling the dog population without using bite-injury follow-up were found to be neither sensitive nor cost-effective.\n\nInterpretationThe low prevalence of rabies, and short window in which disease can be detected, preclude sampling-based surveillance. Instead, active case finding guided by bite-patient triage is needed as elimination is approached. Our proposed methodology is affordable, practical and supports the goal of eliminating human rabies deaths by improving administration of lifesaving post-exposure prophylaxis for genuinely exposed but untreated contacts. Moreover, joint investigations by public health and veterinary workers will strengthen intersectoral partnerships and capacity for control of emerging zoonoses.

epidemiology↗

bioRxiv2016

Modeling HIV disease progression and transmission at population-level: The potential impact of modifying disease progression in HIV treatment programs

IntroductionMathematical models of HIV transmission that incorporate the dynamics of disease progression can estimate the potential impact of adjunctive strategies to antiretroviral therapy (ART) for HIV treatment and prevention. Suppressive treatment of HIV-positive persons co-infected with herpes simplex virus-2 (HSV-2) with valacyclovir, a medication directed against HSV-2, can lower HIV viral load, but the impact of valacyclovir on population HIV transmission has not been estimated.\n\nMethodsWe applied data on CD4 and viral load progression in ART-naive persons studied in two HIV clinical trials to a novel, discrete-time Markov model. We validated our disease progression estimates using data from a trial of home-based HIV counseling and testing in KwaZulu-Natal, South Africa. Finally, we applied our disease progression estimates to a dynamic transmission model estimating the impact of providing valacyclovir to ART-naive individuals to reduce onward transmission of HIV in three scenarios of different ART and valacyclovir population coverage. We assumed that valacyclovir reduced HIV viral load by 1.23 log copies/L, and that persons treated with valacyclovir initiated ART more rapidly when their CD4 fell below 500 due to improved retention in pre-ART care.\n\nResultsThe average duration of HIV infection following acute infection was 9.5 years. The duration of disease after acute infection and before reaching CD4 200 cells/L was 2.53 years longer for females than males. Relative to a baseline of community HIV testing and counseling and ART initiation at CD4 <=500 cells/L, valacyclovir with increased linkage to care resulted in 166,000 fewer HIV infections over ten years, with an incremental cost-effectiveness ratio (ICER) of $4,696 per HIV infection averted. The Test and Treat scenario with 70% ART coverage and no valacyclovir resulted in 202,000 fewer HIV infections at an ICER of $6,579.\n\nConclusionEven when compared with initiation of valacyclovir, a safe drug that reduces HIV viral load, universal treatment for HIV is the optimal strategy for averting new infections and increasing public health benefit. Universal HIV treatment should be pursued by all countries to most effectively and efficiently reduce the HIV burden.

epidemiology↗

bioRxiv2017

Association between urinary biomarkers of total sugars and sucrose intake and BMI in a cross-sectional study

Obesity is an important modifiable risk factors for chronic diseases. While there is increasing focus on the role of dietary sugars, there remains a paucity of data establishing the association between sugar intake and obesity in the general public. The objective of this study was to investigate associations of estimated sugar intake with odds for obesity in a representative samples of English adults. We used data from 434 participants of the 2005 Health Survey of England. Biomarkers for total sugar intake were measured in 24h urine samples and used to estimate intake. Linear and logistic regression analyses were used to investigate associations between estimated intake and measures of obesity (BMI, waist circumference and waist-to-hip ratio) and obesity risk., respectively. Estimated sugars intake was significantly associated with BMI, waist circumference and waist-to-hip ratio, and these associations remained significant after adjustment for estimated protein intake. Estimated sugars intake was also associated with increased odds for obesity based on BMI (OR 1.02; 95% CI 1.00; 1.04 per 10 g), waist-circumference (OR 1.03; 95% CI 1.01; 1.05) and waist-to-hip ratio (OR 1.04; 95% CI 1.02; 1.06); all OR estimates remained significant after adjusting for estimated protein intake. Our results show a significant association between biomarker-estimated total sugars intake and both measures of obesity and obesity risk, confirming positive associations between total sugar intake, measures of obesity and obesity risk. This biomarker could be used to monitor the efficacy of public health interventions.

epidemiology↗

bioRxiv2017

Spatial point pattern analysis of prehospital naloxone administrations

ObjectivesThe increasing problem in the United States with opioid dependence and overdose, often fatal, is well-recognized. As naloxone has only one clinical use--the treatment of opioid overdose--its administration by EMS personnel can serve as a surveillance indicator for opioid overdose. This study uses specific locations of EMS calls, and methods of point pattern analysis, to detect overall spatial clustering among EMS naloxone administrations compared to EMS calls in general.\n\nStudy DesignA cross-sectional study of incident locations of EMS responses in a three-county EMS region in the United States.\n\nMethodsRepeated random samples from the spatial distribution of all EMS calls were used, in a Monte Carlo simulation, to represent the background inhomogeneity of the population. Observed F, G, and inhomogeneous K and L functions from the spatial distribution of naloxone-involved calls were compared to their null sampling distributions obtained from the Monte Carlo simulation.\n\nResultsCases of naloxone administration demonstrated spatial clustering in the range of 0 to 5000 meters, and particularly around 2500 meters, beyond what could be attributable to the spatial heterogeneity of all EMS calls.\n\nConclusionsEfforts to understand the fundamental nature of opioid overdose as a spatial point process could yield innovative public health interventions to control the epidemic.

epidemiology↗

bioRxiv2017

Long-term sustained malaria control leads to inbreeding and fragmentation of Plasmodium vivax populations

The human malaria parasite Plasmodium vivax is resistant to malaria control strategies maintaining high genetic diversity even when transmission is low. To investigate whether declining P. vivax transmission leads to increasing P. vivax population structure that would facilitate elimination, we genotyped samples from a wide range of transmission intensities and spatial scales in the Southwest Pacific, including two time points at one site (Tetere, Solomon Islands) during intensified control. Analysis of 887 P. vivax microsatellite haplotypes from hyperendemic Papua New Guinea (PNG, n = 443), meso-hyperendemic Solomon Islands (n= 420), and hypoendemic Vanuatu (n=24) revealed increasing population structure and multilocus linkage disequilibrium and a modest decline in diversity as transmission decreases over space and time. In Solomon Islands, which has had sustained control efforts for 20 years, and Vanuatu, which has experienced sustained low transmission for many years, significant population structure was observed at different spatial scales. We conclude that control efforts will eventually impact P. vivax population structure and with sustained pressure, populations may eventually fragment into a limited number of clustered foci that could be targeted for elimination.

epidemiology↗

bioRxiv2017

The shape of the contact-density function matters when modelling disease transmission in fluctuating populations

Models of disease transmission in a population with changing densities must assume a relation between infectious contacts and density. Typically, a choice is made between a constant (frequency-dependence) and a linear (density-dependence) contact-density function, but it is becoming increasingly clear that intermediate, nonlinear functions intermediate are more realistic. It is currently not clear however what the exact consequences would be of different contact-density functions in fluctuating populations. By combining field data on rodent host (Mastomys natalensis) demography, experimentally-derived contact-density data, and laboratory and field data Morogoro virus infection dynamics, we explored the effects of different contact-density function shapes on transmission dynamics and invasion/persistence. While invasion and persistence were clearly affected by the shape of the function, the effects on outbreak characteristics such as infection prevalence and seroprevalence were less obvious. This means that it may be difficult to distinguish between the different shapes based on how well models fit to real data. The shape of the transmission-density function should therefore be chosen with care, and is ideally based on existing information such as a previously quantified contact- or transmission-density relationship or the underlying biology of the host species in relation to the infectious agent.

epidemiology↗

bioRxiv2017

Phylodynamics without trees: estimating R0 directly from pathogen sequences

We develop a new tree-free phylodynamic method to estimate the reproduction number (R0) of a pathogen from large numbers of sequences of a pathogen. It is based on the convergence of the cherry-to-tip ratio (CTR) to a constant depending on R0 in supercritical branching trees. It is a tree-free method because tree reconstruction is not required: the number of cherries and the CTR is estimated directly from the sequences using the new computational method Cherries Without Tree (CWT). With simulations, we compare CWT to other methods currently in use. We use the new inference method to estimate R0 from simulated sequences and discuss its accuracy. We explore the potential bias arising from sub-sampling.

epidemiology↗

bioRxiv2017

Infectious Reactivation of Cytomegalovirus Explaining Age-and Sex-Specific Patterns of Seroprevalence

Human cytomegalovirus is a herpes virus with poorly understood transmission dynamics. We here provide quantitative estimates of the transmissibility of primary infection, reactivation, and re-infection using age-and sex-specific antibody response data. The data are optimally described by three distributions of antibody measurements, i.e. uninfected, infected, and infected after reactivation/re-infection. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males is infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males has experienced a reactivation or re-infection episode. Merging the statistical analyses with transmission models, we find that infectious reactivation is key to provide a good fit fit to the data. Estimated reactivation rates increase from low values in children to 2%-6% per year older women. The results advance a hypothesis in which adult-to-adult transmission after infectious reactivation is the main driver of infection.

epidemiology↗

bioRxiv2017

The Negev hospital-university-based (HUB) autism database

Elucidating the heterogeneous etiologies of autism will require investment in comprehensive longitudinal data acquisition from large community based cohorts. With this in mind, we have established a hospital-university-based (HUB) database of autism which incorporates prospective and retrospective data from a large and ethnically diverse population. Here we present initial findings from 188 children who were diagnosed with autism during the first eighteen months of the study. The unique characteristics of this cohort included: significant differences between Bedouin and Jewish children in different risk factors and clinical characteristics; complete birth records for >90% of the children; and a high frequency of consanguineous marriages. Thus, the Negev HUB autism database comprises a remarkably unique resource to study different aspects of autism.

epidemiology↗

bioRxiv2017

A general goodness-of-fit test for survival analysis

Existing goodness-of-fit tests for survival data are either exclusively graphical in nature or only test specific model assumptions, such as the proportional hazards assumption. We describe a flexible, parameter-free goodness-of-fit test that provides a simple numerical assessment of a models suitability regardless of the structure of the underlying model. Intuitively, the goodness-of-fit test utilizes the fact that for a good model early event occurrence is predicted to be just as likely as late event occurrence, whereas a bad model has a bias towards early or late events. Formally, the goodness-of-fit test is based on a novel generalized Martingale residual which we call the martingale survival residual. The martingale survival residual has a uniform probability density function defined on the interval -0.5 to +0.5 if censoring is either absent or accounted for as one outcome in a competing hazards framework. For a good model, the set of calculated residuals is statistically indistinguishable from the uniform distribution, which is tested using the Kolmogorov-Smirnov statistic.

epidemiology↗

bioRxiv2017

A risk assessment framework for seed degeneration: Informing an integrated seed health strategy for vegetatively-propagated crops

Pathogen build-up in vegetative planting material, termed seed degeneration, is a major problem in many low-income countries. When smallholder farmers use seed produced on-farm or acquired outside certified programs, it is often infected. We introduce a risk assessment framework for seed degeneration, evaluating the relative performance of individual and combined components of an integrated seed health strategy. The frequency distribution of management performance outcomes was evaluated for models incorporating biological and environmental heterogeneity, with the following results. (1) On-farm seed selection can perform as well as certified seed, if the rate of success in selecting healthy plants for seed production is high; (2) When choosing among within-season management strategies, external inoculum can determine the relative usefulness of incidence-altering management (affecting the proportion of diseased plants/seeds) and rate-altering management (affecting the rate of disease transmission in the field); (3) Under severe disease scenarios, where it is difficult to implement management components at high levels of effectiveness, combining management components can produce synergistic benefits and keep seed degeneration below a threshold; (4) Combining management components can also close the yield gap between average and worst-case scenarios. We also illustrate the potential for expert elicitation to provide parameter estimates when data are unavailable.

epidemiology↗

bioRxiv2017

Asian lineage of Zika virus RNA pseudoknot may induce ribosomal frameshift and produce a new neuroinvasive protein ZIKV-NS1’

Zika virus (ZIKV) is a threat to humanity, and understanding its neuroinvasiveness is a major challenge. Microcephaly observed in neonates in Brazil is associated with ZIKV that belongs to the Asian lineage. What distinguishes the neuroinvasiveness between the RNA lineages from Asia and Africa is still unknown. Here we identify an aspect that may explain the different behavior between the two lineages. The distinction between the two groups is the occurrence of an alternative protein NS1 (ZIKV-NS1), which happens through a pseudoknot in the virus RNA that induces a ribosomal frameshift. Presence of NS1 protein is also observed in other Flavivirus that are neuroinvasive, and when NS1 production issuppressed, neuroinvasiveness is reduced.1 This evidence gives grounds to suggest that the ZIKV-NS1 occurring in the Asian lineage is responsible for neuro-tropism, which causes the neuro-pathologies associated with ZIKV infection, of which microcephaly is the most dev astating. The existence of ZIKV-NS1, which only exists in the Asian lineage, was inferred through bioinformatic methods, and it has yet to be experimentally observed. If its occurrence is confirmed, it will be a potential target in fighting the neuro-diseases associated with ZIKV.

epidemiology↗

bioRxiv2017

Education and coronary heart disease: a Mendelian randomization study

ObjectivesTo determine whether educational attainment is a causal risk factor in the development of coronary heart disease.\n\nDesignMendelian randomization study, where genetic data are used as proxies for education, in order to minimize confounding. A two-sample design was applied, where summary level genetic data was analysed from two publically available consortia.\n\nSettingIn the main analysis, we analysed genetic data from two large consortia (CARDIoGRAM and SSGAC), comprising of 112 cohorts from predominantly high-income countries. In addition, we also analysed genetic data from 7 additional large consortia, in order to identify putative causal mediators.\n\nParticipantsThe main analysis was of 589 377 men and women, predominantly of European origin.\n\nExposureA one standard deviation increase in the genetic predisposition towards higher education (i.e. 3.6 years of additional schooling). This was measured by 162 genetic variants that have been previously associated with education.\n\nMain outcomeCombined fatal and nonfatal coronary heart disease (63 746 events).\n\nResults3.6 years of additional education lowered the risk of coronary heart disease by a third (odds ratio = 0.67, 95% confidence interval [CI], 0.59 to 0.77, p=0.01). Equivalent increases in education were also causally associated with reductions in smoking, BMI and improvements in blood lipid profiles.\n\nConclusionsMore time spent in education is causally associated with a large reduction in the risk of coronary heart disease. This may be partly explained by changes to smoking, BMI and a blood lipids. These findings offer support for policy interventions that increase education, in order to also reduce the burden of cardiovascular disease.

epidemiology↗

bioRxiv2017

Disease implications of animal social organization and network structure - a quantitative analysis

O_LIThe disease costs of sociality have largely been understood through the link between group size and transmission. However, infectious disease spread is driven primarily by the social organization of interactions in a group and not its size.\nC_LIO_LIWe used statistical models to review the social network organization of 47 species, including mammals, birds, reptiles, fish and insects by categorizing each species into one of three social systems, relatively solitary, gregarious and socially hierarchical. Additionally, using computational experiments of infection spread, we determined the disease costs of each social system.\nC_LIO_LIWe find that relatively solitary species have large variation in number of social partners, that socially hierarchical species are the least clustered in their interactions, and that social networks of gregarious species tend to be the most fragmented. However, these structural differences are primarily driven by weak connections, which suggests that different social systems have evolved unique strategies to organize weak ties.\nC_LIO_LIOur synthetic disease experiments reveal that social network organization can mitigate the disease costs of group living for socially hierarchical species when the pathogen is highly transmissible. In contrast, highly transmissible pathogens cause frequent and prolonged epidemic outbreaks in gregarious species.\nC_LIO_LIWe evaluate the implications of network organization across social systems despite methodological challenges, and our findings offer new perspective on the debate about the disease costs of group living. Additionally, our study demonstrates the potential of meta-analytic methods in social network analysis to test ecological and evolutionary hypotheses on cooperation, group living, communication, and resilience to extrinsic pressures.\nC_LI

epidemiology↗