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bioRxiv2018

A spatio-temporal individual-based network framework for West Nile virus in the USA: spreading pattern of West Nile virus

West Nile virus (WNV)--a mosquito-borne arbovirus-- entered the USA through New York City in 1999 and spread to the contiguous USA within three years while transitioning from epidemic outbreaks to endemic transmission. The virus is transmitted by vector competent mosquitoes and maintained in the avian populations. WNV spatial distribution is mainly determined by the movement of residential and migratory avian populations. We developed an individual-level heterogeneous network framework across the USA with the goal of understanding the long-range spatial distribution of WNV. To this end, we proposed three distance dispersal kernels model: 1) exponential--short-range dispersal, 2) power-law--long-range dispersal in all directions, and 3) power-law biased by flyway direction--long-range dispersal only along established migratory routes. To select the appropriate dispersal kernel we used the human case data and adopted a model selection framework based on approximate Bayesian computation with sequential Monte Carlo sampling (ABC-SMC). From estimated parameters, we find that the power-law biased by flyway direction kernel is the best kernel to fit WNV human case data, supporting the hypothesis of long-range WNV transmission is mainly along the migratory bird flyways. Through extensive simulation from 2014 to 2016, we proposed and tested hypothetical mitigation strategies and found that mosquito population reduction in the infected states and neighboring states is potentially cost-effective.\n\nAuthor summaryThe underlying pattern of West Nile virus (WNV) geographic spread across the United States is not completely clear, which is a necessary step for continental or state level mitigation strategies to reduce WNV transmission. We report a network model that explains the geographic spread of WNV in the United States. West Nile virus is a mosquito-borne pathogen that infects many avian species with different movement ranges. From our research, we found that migration patterns and routes play an essential role in the WNV spatial distribution. The virus spreads in all directions at short distances because of local birds and short-distance migratory birds. However, the virus also disperses long distances along the avian migratory routes. Our model is designed to be flexible and therefore can be used to explore spreading patterns of other infectious diseases in other geographic locations.

epidemiology↗

bioRxiv2018

Antibodies against egg- and cell-grown influenza A(H3N2) viruses in adults hospitalized during the 2017-2018 season

BackgroundThe 2017-2018 US influenza season was severe with low vaccine effectiveness. Circulating A(H3N2) viruses from multiple genetic groups were antigenically similar to cell-grown vaccine strains. However, most influenza vaccines are egg-propagated.\n\nMethodsSerum was collected shortly after illness onset from 15 PCR confirmed A(H3N2) infected cases and 15 uninfected (controls) hospitalized adults enrolled in an influenza vaccine effectiveness study.\n\nGeometric mean titers against egg- and cell-grown A/Hong Kong/4801/2014 A(H3N2) vaccine strains and representative circulating viruses (including A/Washington/16/2017) were determined by microneutralization (MN) assays. Independent effects of strain-specific titers on susceptibility were estimated by logistic regression.\n\nResultsMN titers against egg-A/Hong Kong were significantly higher among those who were vaccinated (MN GMT: 173 vs 41; P = 0.01). However, antibody titers to cell-grown viruses were much lower in all individuals (P>0.05) regardless of vaccination. In unadjusted models, a 2-fold increase in MN titers against egg-A/Hong Kong was not significantly protective against infection (29% reduction; p=0.09), but a similar increase in cell-A/Washington titer (3C.2a2) was protective (60% reduction; p=0.02). A similar increase in egg-A/Hong Kong titer was not significantly associated with odds of infection when adjusting for MN titers against A/Washington (15% reduction; P=0.61). A 54% reduction of odds of infection was observed with a 2-fold increase in A/Washington (not significant; P=0.07), adjusted for egg-A/Hong Kong titer.\n\nConclusionAlthough individuals vaccinated in 2017-2018 had high antibody titers against the egg-adapted vaccine strain, antibody responses to cell-grown circulating viruses may not be sufficient to provide protection, likely due to egg-adaptation in the vaccine.

epidemiology↗

bioRxiv2018

Comparative validation of breast cancer risk prediction models and projections for future risk stratification

BackgroundWell-validated risk models are critical for risk stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) tool for comparative model validation of five-year risk of invasive breast cancer in a prospective cohort, and to make projections for population risk stratification.\n\nMethodsPerformance of two recently developed models, iCARE-BPC3 and iCARE-Lit, were compared with two established models (BCRAT, IBIS) based on classical risk factors in a UK-based cohort of 64,874 women (863 cases) aged 35-74 years. Risk projections in US White non-Hispanic women aged 50-70 years were made to assess potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS).\n\nResultsThe best calibrated models were iCARE-Lit (expected to observed number of cases (E/O)=0.98 (95% confidence interval [CI]=0.87 to 1.11)) for women younger than 50 years; and iCARE-BPC3 (E/O=1.00 (0.93 to 1.09)) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify ~500,000 women at moderate to high risk (>3% five-year risk). Additional information on MD and a PRS based on 172 variants is expected to increase this to ~3.6 million, and among them, ~155,000 invasive breast cancer cases are expected within five years.\n\nConclusionsiCARE models based on classical risk factors perform similarly or better than BCRAT or IBIS. Addition of MD and PRS can lead to substantial improvements in risk stratification. Independent prospective validation of integrated models is needed prior to clinical evaluation risk stratified breast cancer screening and prevention.

epidemiology↗

bioRxiv2018

Evidence that poor HAART adherence has a great impact on HIV/AIDS treatment failure more than severity of illness and opportunity of infection in Ethiopia: Systematic review and meta-analysis

BackgroundThe pooled burden of HIV treatment failure and its associated factors in Ethiopian context is required to provide evidence towards renewed ambitious future goal.\n\nMethodsPubMed, Web of Science, Scopus, Google Scholar, and Ethiopian Universities (University of Gondar and Addis Ababa University) online repository library were used to get the research articles. I-squared statistics was used to see heterogeneity. Publication bias was checked by Eggers regression test. A meta-analysis using the DerSimonian-Laird random-effects model was employed to estimate the overall prevalence of treatment failure. Subgroup analyses based on the geographical location of the study, age of study population, type of treatment failure, and study design were conducted to see variation in outcomes. The sensitivity analysis was also employed to see whether an outlier result found in the included studies.\n\nResultsOverall HIV treatment failure found to be 15.9% (95% CI: 11.6%-20.1%). HIV treatment failure was 10.2% (6.9%-13.6%) using immunological definition, 5.6% (95% CI: 2.9%-8.3%) using virological definition, and 6.3% (4.6%-8.0%) using clinical definition. Poor HAART adherence (AOR= 8.5; 95% CI: 4.1-12.8), severity of illness (as measured by WHO clinical stage III/IV (AOR=1.9; 95% CI: 1.3-2.6), and presence of opportunistic infections (AOR=1.8; 95% CI: 1.2-2.4) were significantly associated with HIV treatment failure.\n\nConclusionsHIV treatment failure in Ethiopia found to be high and differed by adherence level, severity of illness, and presence of opportunistic infection. HIV intervention programs, such as behavioral intervention is required to sustain HIV treatment adherence and improve treatment success as a result.\n\nProtocol RegistrationIt has been registered in the PROSPERO database (CRD42018100254).

epidemiology↗

bioRxiv2018

Prevalence and correlates of anemia among children aged 6-23 months in Wolaita Zone, Southern Ethiopia

BackgroundAnemia, the worlds most common micro-nutrient deficiency disorder, can affect a person at any time and at all stages of life, although children aged 6 -23 months are particularly at higher risk. If left untreated, it adversely affects the health, cognitive development, school achievement, and work performance. However, littlewas investigated among young children in Sub-Saharan countries including Ethiopia. This research aimed to investigate its magnitude and correlates to address the gap and guide design of evidence based intervention.\n\nMethodsA community-based cross-sectional study was conducted from May -June 2016 in rural districts of Wolaita Zone. Multi-stage sampling technique was applied to select 990 mother-child pairs. Socio-demography, health and nutritional characteristics were collected by administering interview type questionnaire to mothers/care-givers. Blood samples were taken to diagnose anemia by using HemoCue device, and status was determined using cut-offs used for children aged 6-59 months. Hemoglobin concentration below 11.0 g/dl was considered anemic. Data were analyzed with Statav 14. Bivariate and multivariable logistic regressions were applied to identify candidate and predictor variables respectively. Statistical significance was determined at p-value < 0.05 at 95% confidence interval.\n\nResultsThe mean hemoglobin level of children was 10.44{+/-}1.3g/dl, and 65.7% of them were anemic. Among anemic children, 0.4% were severely anemic (<7.0g/dl), while 28.1% and 37.2% were mildly (10.0-10.9g/dl) and moderately (7.0-9.9g/dl) anemic, respectively. In the multivariable analysis, having maternal age of 35 years and above (AOR=1.96), being government employee (AOR=0.29),being merchant (AOR= 0.43) and other occupation (AOR=3.17) were correlated with anemia in children in rural Wolaita. Similarly, receiving antihelminthic drugs (AOR= 0.39), being female child (AOR= 1.76), consuming poor dietary diversity (AOR=1.40), and having moderate household food insecurity (AOR=1.72) were associated with anemia in rural Wolaita.\n\nConclusionA large majority of children in the rural Wolaita were anemic and the need for proven public health interventions such as food diversification, provision of anti-helminthic drugs and ensuring household food security is crucial. In addition, educating women on nutrition and diet diversification, as well as helping them with alternative sources of income might be interventions in the study area.

epidemiology↗

bioRxiv2018

Phenotypic and genotypic resistance to commonly used insecticides in Aedes aegypti among four cities in southern Ecuador

Insecticide resistance (IR) can undermine efforts to control vector species of public health importance. Aedes aegypti is the main vector of resurging diseases in the Americas such as yellow fever and dengue, as well as recently emerging chikungunya and Zika viruses, which have caused unprecedented epidemics in the region. Vector control remains the primary public health intervention to prevent outbreaks of Aedes transmitted diseases. In many high-risk regions, like southern Ecuador, we have limited information on IR in Ae. aegypti. In this study, IR status in Ae. aegypti was measured across four cities in El Oro Province in Ecuador using phenotypic assays and genetic screening for alleles associated with resistance to pyrethroid insecticides. Bottle bioassays showed significant inter-seasonal variation in resistance to deltamethrin, a pyrethroid insecticide commonly used by the Ministry of Health, and alpha cypermethrin, as well as differences in deltamethrin resistance between cities. There was also a significant difference in phenotypic response to the organophosphate, Malathion, between two of the cities during the second sampling season. Genotyping showed moderate to high frequencies of the V1016I and F1534C resistance alleles in all four cites. Frequency of resistance genotypes varied significantly between cities in the first sampling season, and not in the later seasons, suggesting a possible selective response to vector control activity. Overall, resistance levels were highest in Machala, a city where dengue is hyperendemic and where insecticide use has historically been more intense than in the other cities included in the study. Despite statistically significant evidence that resistance alleles conferred phenotypic resistance, there was not precise correspondence between these indicators. We found that 17.6% of F1534C and 45.6% of V1016I mutant mosquitoes were susceptible in the bottle bioassays. This study shows there is spatiotemporal variability in IR in southern Ecuador, and serves as an initial examination of the genotypic and phenotypic indicators of IR in this region, providing important information to guide the vector control interventions by the public health sector.

epidemiology↗

bioRxiv2018

MR-pheWAS with stratification and interaction: Searching for the causal effects of smoking heaviness identified an effect on facial aging

Mendelian randomization (MR) is an established approach for estimating the causal effect of an environmental exposure on a downstream outcome. The gene x environment (GxE) study design can be used within an MR framework to determine whether MR estimates may be biased if the genetic instrument affects the outcome through pathways other than via the exposure of interest (known as horizontal pleiotropy). MR phenome-wide association studies (MR-pheWAS) search for the effects of an exposure, and a recently published tool (PHESANT) means that it is now possible to do this comprehensively, across thousands of traits in UK Biobank. In this study, we introduce the GxE MR-pheWAS approach, and search for the causal effects of smoking heaviness - stratifying on smoking status (ever versus never) - as an exemplar. If a genetic variant is associated with smoking heaviness (but not smoking initiation), and this variant affects an outcome (at least partially) via tobacco intake, we would expect the effect of the variant on the outcome to differ in ever versus never smokers. If this effect is entirely mediated by tobacco intake, we would expect to see an effect in ever smokers but not never smokers. We used PHESANT to search for the causal effects of smoking heaviness, instrumented by genetic variant rs16969968, among never and ever smokers respectively, in UK Biobank. We ranked results by: 1) strength of effect of rs16969968 among ever smokers, and 2) strength of interaction between ever and never smokers. We replicated previously established causal effects of smoking heaviness, including a detrimental effect on lung function and pulse rate. Novel results included a detrimental effect of heavier smoking on facial aging. We have demonstrated how GxE MR-pheWAS can be used to identify causal effects of an exposure, while simultaneously assessing the extent that results may be biased by horizontal pleiotropy.\n\nAuthor summaryMendelian randomization uses genetic variants associated with an exposure to investigate causality. For instance, a genetic variant that relates to how heavily a person smokes has been used to test whether smoking causally affects health outcomes. Mendelian randomization is biased if the genetic variant also affects the outcome via other pathways. We exploit additional information - that the effect of heavy smoking only occurs in people who actually smoke - to overcome this problem. By testing associations in ever and never smokers separately we can assess whether the genetic variant affects an outcome via smoking or another pathway. If the effect is entirely via smoking heaviness, we would expect to see an effect in ever but not never smokers, and this would suggest that smoking causally influences the outcome. Previous Mendelian randomization studies of smoking heaviness focused on specific outcomes - here we searched for the causal effects of smoking heaviness across over 18,000 traits. We identified previously established effects (e.g. a detrimental effect on lung function) and novel results including a detrimental effect of heavier smoking on facial aging. Our approach can be used to search for the causal effects of other exposures, where the exposure only occurs in known subsets of the population.

epidemiology↗

bioRxiv2018

TREATMENT OUTCOME OF DIABETIC KETOACIDOSIS AMONG PATIENTS ATENDING GENERAL HOSPITAL IN NORTH-WEST ETHIOPIA: HOSPITAL BASED STUDY

BackgroundDiabetic ketoacidosis is an acute life-threatening complication of diabetes mellitus. There was limited data on level of in-hospital mortality, hospital stay and factors associated with length of hospital stay among diabetic patients admitted to diabetic ketoacidosis at Debretabor General Hospital.\n\nObjectiveThe aim of the study was to determine the length of hospital stay and in-hospital mortality of diabetic ketoacidosis patients and to assess determinants of long hospital stay among diabetic patients admitted with Diabetic ketoacidosis at Debretabor General Hospital.\n\nMethodA retrospective study was conducted at Debretabor General Hospital from June 1to 30, 2018. Participants included in the study were all diabetic patients with diabetic ketoacidosis admitted to the hospital from August 2010 to May 31, 2018 whose medical records contained complete pertinent data. The primary outcome was to determine the length of hospital stay and in-hospital mortality of diabetic ketoacidosis patients. All the statistical data was carried out using Statistical Package for Social Sciences (SPSS). Descriptive statistics was presented using means with standard deviation and percentages.\n\nResultA total of 387 patients medical records contained pertinent complete information included in this study. Mean age of the patients was 33.30{+/-} 14.96 years. The majority of patients were females 244 (63.0%). The mean length of hospital stay was 4.64({+/-}2.802) days. About twenty percent 79(20.41%) patients had long hospital stay (>7days). The majority 370 (95.60%) of patients improved and discharged and 17 (4.40%) patients died in the hospital. patients who had mild DKA; AOR: 0.16 [0.03-0.78] and patients between the age of 35-44years, AOR: 0.125[0.017-0.92] had reduced length of hospital stay. further, patients with DKA precipitated by infection were 4.59 times more likely to have long hospital stay than patients with DKA precipitated by unknown causes; AOR 4.59[1.08-19.42].\n\nConclusionsIn the current study, the mean length of hospital stay was around five days. About twenty percent patients had long hospital stay. Nearly ninety five percent of patientsimproved and discharged. The presence of infection, frequent rebound hyperglycemia and severity of DKA were the major determinants of long hospital stay.

epidemiology↗

bioRxiv2018

Evaluation of the NCCN guidelines using the RIGHT Statement and AGREE II instrument: a cross-sectional review.

IntroductionRobust, clearly reported clinical practice guidelines (CPGs) are essential for evidence-based clinical practice. The Reporting Items for practice Guidelines in HealThcare (RIGHT) statement and Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument were published to improve the methodological and reporting quality in healthcare CPGs.\n\nMethodsWe applied the RIGHT statement checklist and AGREE II instrument to 48 National Comprehensive Cancer Network (NCCN) guidelines. Our primary objective was to assess the adherence to RIGHT and AGREE II items. Since neither RIGHT nor AGREE-II can judge the clinical usefulness of a guideline, our study is designed to only focus on the methodological and reporting quality of each guideline.\n\nResultsThe NCCN guidelines demonstrated notable strengths and weaknesses. For example, RIGHT statement items 19 (conflicts of interest), 7b (description of subgroups), and 13a (clear, precise recommendations) were fully reported in all guidelines. However, the guidelines inconsistently incorporated patient values and preferences and cost, nor did they consistently describe the method for assessing the quality and certainty of evidence. Regarding the AGREE II instrument, the NCCN guidelines scored highly on the domains 4 (clear, precise recommendations) and 6 (handling of conflicts of interest), but lowest on domain 2 (inclusion of all relevant stakeholders).\n\nConclusionsIn this investigation we found that NCCN CPGs demonstrate key strengths and weaknesses with respect to the reporting of key items essential to CPGs. We recommend the continued use of NCCN guidelines and adherence to the RIGHT and AGREE II items. Doing so serves to improve the evidence delivered to healthcare providers, thus potentially improving patient care.

epidemiology↗

bioRxiv2018

Rapid statistical methods for inferring intra- and inter-hospital transmission of nosocomial pathogens from whole genome sequence data

Whole genome sequence (WGS) data for bacterial pathogens can provide evidence as to the source of nosocomial infection, and more specifically the ability to distinguish between intra- and inter-hospital transmission. This is currently achieved either through using SNP thresholds, which can lack statistical robustness, or by constructing phylogenetic trees, which can be computationally expensive and difficult to interpret. Here we compare two alternative statistical approaches using 1022 genomes of methicillin resistant Staphylococcus aureus (MRSA) clone ST22. In 71% of cases both methods predict the same hospital origin, which is also supported by the ML tree. Robust assignments are divided approximately equally between intra-hospital transmission and inter-hospital transmission. Our approaches are rapid and produce intuitive output that could inform on immediate infection control priorities, as well as providing long-term data on inter-hospital transmission networks. We discuss the strengths and weakness of our methods, and the generalisability of this approach.\n\nOne Sentence SummaryWe present rapid statistical methods for distinguishing intra- versus inter-hospital transmission of bacterial pathogens using whole genome sequence data; these methods do not require the use of SNP thresholds or the generation and interpretation of phylogenetic trees.

epidemiology↗

bioRxiv2018

Sampling for disease absence-deriving informed monitoring from epidemic traits

Monitoring for disease requires subsets of the host population to be sampled and tested for the pathogen. If all the samples return healthy, what are the chances the disease was present but missed? In this paper, we developed a statistical approach to solve this problem considering the fundamental property of infectious diseases: their growing incidence in the host population. The model gives an estimate of the incidence probability density as a function of the sampling effort, and can be reversed to derive adequate monitoring patterns ensuring a given maximum incidence in the population. We then present an approximation of this model, providing a simple rule of thumb for practitioners. The approximation is shown to be accurate for a sample size larger than 20, and we demonstrate its use by applying it to three plant pathogens: citrus canker, bacterial blight and grey mould.

epidemiology↗

bioRxiv2018

Translating surveillance data into incidence estimates

Monitoring a population for a disease requires the hosts to be sampled and tested for the pathogen. This results in sampling series from which to estimate the disease incidence, i.e. the proportion of hosts infected. Existing estimation methods assume that disease incidence is not changing between monitoring rounds, resulting in underestimation of the disease incidence. In this paper we develop an incidence estimation model accounting for epidemic growth with monitoring rounds sampling varying incidence. We also show how to accommodate the asymptomatic period characteristic to most diseases. For practical use, we produce an approximation of the model, which is subsequently shown accurate for relevant epidemic and sampling parameters. Both the approximation and the full model are applied to stochastic spatial simulations of epidemics. The results prove their consistency for a very wide range of situations.

epidemiology↗

bioRxiv2018

Detection of multiple circulating Leishmania species in Lutzomyia longipalpis in the city of Governador Valadares, southeastern Brazil

BackgroundLeishmaniasis encompasses a group of diverse clinical diseases caused by protozoan parasites of the Leishmania genus. This disease is a major public health problem in the New World affecting people exposed in endemic regions. The city of Governador Valadares (Minas Gerais/Brazil) is a re-emerging area for visceral leishmaniasis, with 191 human cases reported from 2008 to 2017 and a lethality rate of 14.7%. The transmission of the parasite occurs intensely in this region with up to 22% of domestic dogs with positive serology for the visceral form. Lu. longipalpis is one of the most abundant sand fly species in this area. Despite this scenario, so far there is no information regarding the circulating Leishmania species in the insect vector Lutzomyia longipalpis in this focus.\n\nMethodology/Principal FindingsWe collected 616 female Lutzomyia longipalpis sand flies between January and September 2015 in the Vila Parque Ibituruna neighborhood (Governador Valadares/MG), which is located on a transitional area between the sylvatic and urban environments with residences built near a preserved area. After DNA extraction of individual sand flies, the natural Leishmania infections in Lu. longipalpis were detected by end-point PCR, using primers derived from kDNA sequences, specific for L. (Leishmania) or L. (Viannia) subgenus. The sensitivity of these PCR reactions was 0.1 pg of DNA for each Leishmania subgenus and the total infection rate of 16.2% (100 positive specimens). Species-specific PCR detected the presence of multiple Leishmania species in infected Lu. longipalpis specimens in Governador Valadares, including L. amazonensis (n=3), L. infantum (n=28), L. (Viannia) spp. (n=20), coinfections with L. infantum and L. (Viannia) spp. (n=5), and L. (Leishmania) spp (n=44).\n\nConclusionsOur results demonstrate that multiple Leishmania species circulate in Lu. longipalpis in Governador Valadares and reveal a potential increasing risk of transmission of the different circulating parasite species. This information is a key factor for planning surveillance and effective control strategies against leishmaniasis in this endemic focus.\n\nAuthor summaryLeishmaniasis is a neglected tropical disease transmitted to mammals by the bite of sand flies infected with parasites of the Leishmania genus. This disease affects millions of people in various regions of the world, including Brazil. The municipality of Governador Valadares (Minas Gerais/Brazil) is a re-emergent focus of intense transmission of leishmaniasis, with a high number of human cases and a high prevalence of infected domestic dogs. To develop better leishmaniasis control strategies for the region, we performed a surveillance study of Lu. longipalpis, the main vector of visceral leishmaniasis in Brazil, and identified circulating species of Leishmania in this insect vector. We estimate that the natural infection rate of Lu. longipalpis for these parasites was of 16.2% in the study area. We also detected the presence of multiple circulating Leishmania species (L. amazonensis, L. infantum and Viannia subgenus) in Lu. longipalpis in Governador Valadares city, including 5 sand flies coinfected with L. infantum and L. (Viannia). Thus, our results reinforce the need for a rigid and systematic control of the sand flies monitoring in this area, due to the potential risk of transmission of different species of the Leishmania parasites.

epidemiology↗

bioRxiv2018

Associations between environmental breast cancer risk factors and DNA methylation-based risk-predicting measures

BackgroundGenome-wide average DNA methylation (GWAM) and epigenetic age acceleration have been suggested to predict breast cancer risk. We aimed to investigate the relationships between these putative risk-predicting measures and environmental breast cancer risk factors.\n\nMethodsUsing the Illumina HumanMethylation450K assay methylation data, we calculated GWAM and epigenetic age acceleration for 132 female twin pairs and their 215 sisters. Linear regression was used to estimate associations between these risk-predicting measures and multiple breast cancer risk factors. Within-pair analysis was performed for the 132 twin pairs.\n\nResultsGWAM was negatively associated with number of live births, and positively with age at first live birth (both P<0.05). Epigenetic age acceleration was positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche, and negatively with age at first live birth (all P<0.05), and the associations with BMI, alcohol drinking and age at first live birth remained in the within-pair analysis.\n\nConclusionsThis exploratory study shows that lifestyle and hormone-related breast cancer risk factors are associated with DNA methylation-based measures that could predict breast cancer risk. The associations of epigenetic age acceleration with BMI, alcohol drinking and age at first live birth are unlikely to be due to familial confounding.

epidemiology↗

bioRxiv2018

Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

BackgroundPostmarketing commitments are clinical studies that drug sponsors agree to conduct at the time of FDA approval, but which are not required by statute or regulation. The objective of this study was to determine the characteristics, completion, and dissemination of postmarketing commitments agreed upon by sponsors at first FDA approval.\n\nMethodsWe performed a cross-sectional analysis of postmarketing commitments for new drugs and biologics approved 2009-2012. Using public FDA documents, ClinicalTrials.gov, and Scopus, we determined postmarketing commitments and their characteristics known at the time of FDA approval; number of postmarketing commitments subject to reporting requirements, for which FDA is required to make study status information available to the public (\"506B studies\"), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials, with follow-up through July 2018.\n\nResultsAmong 110 novel drugs and biologics approved by the FDA between 2009-2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 271 (81.9%) were non-human subjects research, predominantly chemistry, manufacturing, and controls studies; 49 (14.8%) were clinical trials (33 new and 16 ongoing trials for which follow-up results would be reported). Study descriptions for the new clinical trials often lacked information to establish study design features. Of the 89 (26.9%) 506B studies subject to public reporting requirements, of which 42 were clinical trials, 59 (66.3%) did not have an up-to-date status provided by FDA. Nearly all new clinical trials (28 of 31, 90.3%) were registered on ClinicalTrials.gov; of the 23 registered trials that were completed or terminated, 22 (95.7%) had reported results. Only half (14 of 29, 48.3%) of completed or terminated clinical trials, registered or unregistered, were published in peer-reviewed journals. Conclusions: The majority of postmarketing commitments agreed to by sponsors at the time of FDA approval for novel drugs and biologics approved between 2009-2012 were chemistry, manufacturing, and controls studies. While only 15% were clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, despite FDA public reporting requirements, up-to-date study status information was often unavailable for 506B studies.

epidemiology↗

bioRxiv2018

Causal Association between Birth Weight and Adult Diseases: Evidence from a Mendelian Randomisation Analysis

BackgroundIt has long been hypothesized that birth weight has a profound long-term impact on individual predisposition to various diseases at adulthood: a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight. Determining the causal impact of birth weight on various adult diseases through traditional randomised intervention studies is a challenging task.\n\nMethodsMendelian randomisation was employed and multiple genetic variants associated with birth weight were used as instruments to explore the relationship between 21 adult diseases and 38 other complex traits from 37 large-scale genome-wide association studies up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses and simulations.\n\nResultsAmong the 21 adult diseases, three were identified to be inversely causally affected by birth weight with a statistical significance level passing the Bonferroni corrected significance threshold. The measurement unit of birth weight was defined as its standard deviation (i.e. 488 grams), and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D) and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17 - 1.53, p = 1.54E-5], 1.30 (95% CI 1.13 - 1.51, p = 3.31E-4), 1.41 (95% CI 1.15 - 1.73, p = 1.11E-3) and 1.54 (95% CI 1.25 - 1.89, p = 6.07E-5), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as inverse causation. In addition, analysis on 38 additional complex traits found that the inverse causal association between birth weight and CAD/MI/T2D was not likely to be mediated by other risk factors such as blood-pressure related traits and adult weight.\n\nConclusionsThe results suggest that lower birth weight is causally associated with an increased risk of CAD, MI and T2D in later life, supporting the fetal origins of adult diseases hypothesis.

epidemiology↗

bioRxiv2018

Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations.

epidemiology↗

bioRxiv2018

Benefit-cost analysis of the policy of mandatory annual rabies vaccination of domestic dogs in rabies-free Japan

Japan is one of the few rabies-free countries/territories which implement the policy of mandatory vaccination of domestic dogs. In order to assess the economic efficiency of such policy in reducing the economic burden of a future canine rabies outbreak in Japan, a benefit-cost analysis (BCA) was performed using probabilistic decision tree modelling. Input data derived from simulation results of published mathematical model, field investigation conducted by the authors at prefectural governments, literature review, international or Japanese database and empirical data of rabies outbreaks in other countries/territories. The current study revealed that the annual costs of implementing the current vaccination policy would be US$160,472,075 (90% prediction interval [PI]: $149,268,935 - 171,669,974). The economic burden of a potential canine rabies outbreak in Japan were estimated to be US$1,682,707 (90% PI: $1,180,289 - 2,249,283) under the current vaccination policy, while it would be US$5,019,093 (90% PI: $3,986,882 - 6,133,687) under hypothetical abolition of vaccination policy, which is 3-fold higher. Under a damage-avoided approach, the annual benefits of implementing the current vaccination policy in expected value were estimated to be US$85.75 (90% PI: $55.73 - 116.89). The benefit-cost ratio (BCR) was estimated to be 5.35 x 10-7 (90% PI: 3.46 x 10-7 - 7.37 x 10-7), indicating that the implementation of the current policy is very economically inefficient for the purpose of reducing the economic burden of a potential canine rabies outbreak. In worse-case scenario analysis, the BCR would become above 1 (indicating economic efficiency) if the risk of rabies introduction increased to 0.04 corresponding to a level of risk where rabies would enter Japan in 26 years while the economic burden of a rabies outbreak under the abolition of vaccination policy increased to $7.53 billion. Best-case analysis further revealed that the economic efficiency of the current policy could be improved by decreasing the vaccination price charged to dog owners, relaxing the frequency of vaccination to every two to three years and implementing the policy on a smaller scale, e.g. only in targeted prefectures instead of the whole Japan.

epidemiology↗