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bioRxiv2018

Investigating the probability of establishment of Zika virus and detection through mosquito surveillance under different temperature conditions

Because of the increasing threat that Zika virus (ZIKV) poses to extra-tropical regions due to increased global travel, there is a need for better understanding of the effect(s) of temperature on the establishment potential of ZIKV within these subtropical, temperate, and/or seasonal Ae. aegypti populations. The first step to determining risk establishment of ZIKV in these regions is to assess ZIKVs ability to infect mosquitoes at less tropical temperatures, and thus be detected through common surveillance programs. To that end, the effect of two rearing temperatures (RT) and extrinsic incubation temperatures (EIT) on infection and dissemination rates was evaluated, as well as the interactions of such. Total, there were four combinations (RT24-EIT24, RT24-DEI28, RT28-EIT24, RT28- EIT28). Further, a stochastic SEIR framework was adapted to determine whether observed data could lead to differential success of establishment of ZIKV in naive mosquito populations. There was no consistent pattern in significant differences found across treatments for either infection or dissemination rates (p>0.05), where only a significant difference was found in infection rates between RT24- EIT24 (44%) and RT28-EIT24(82.6%). Across all temperature conditions, the model predicted between a 77.3% and 93.1% chance of successful establishment of ZIKV in naive mosquito populations under model assumptions. Further, the model predicted between 4.1% and 46.7% chance of at least one mosquito developing a disseminated infection, depending on temperature conditions, despite no significant differences in the experimental data. These results indicate that 1) there is no straightforward relationship between RT, EIT, and infection/dissemination rates for ZIKV, similar to what has been reported for DENV, 2) in more temperate climates, ZIKV may still have the ability to establish in populations of Ae. aegypti, and 3) despite a lack of statistical differences in observed experimental data, model predictions indicate that the interplay of rearing and extrinsic incubation temperatures may still alter the kinetics of ZIKV within the mosquito enough to affect numbers of infected/disseminated mosquitoes and the associated probability of detection through surveillance programs.

epidemiology↗
bioRxiv2018

Trends in millennial adolescent mental health and health related behaviours over ten years: a population cohort comparison study

BackgroundThere is evidence that mental health problems are increasing and substance use behaviours are decreasing. This paper aimed to investigate recent trends in mental ill-health and health-related behaviours in two cohorts of UK adolescents in 2005 and 2015.\n\nMethodTrends in harmonised mental ill-health (depressive symptoms, self-harm, anti-social behaviours, parent reported difficulties) and health related behaviours (substance use, weight, weight perception, sleep, sexual intercourse) were examined at age 14 in two UK birth cohorts; Avon Longitudinal Study of Parents and Children (ALSPAC, N=5627, born 1991-92) and Millennium Cohort Study (MCS, N=11318, born 2000-02). Prevalences and trend estimates are presented unadjusted and using propensity score matching and entropy balancing.\n\nResultsDepressive symptoms (9% to [~]15%) and self-harm (11.8% to [~]14.5%) increased over the 10 years. Parent-reported emotional difficulties, conduct problems, hyperactivity and peer problems were higher in 2015 compared to 2005 (5.7 - 9% to 9 - 18%).Conversely, substance use (tried smoking 9% to 3%; tried alcohol 52% to [~]43%, cannabis 4.6% to [~]4%), sexual activity (2% to [~]1%) and anti-social behaviours (6.2 - 40.1% to 1.6 - 28%) were less common or no different. Adolescents in 2015 were spending less time sleeping, had higher BMIs and a greater proportion perceived themselves as overweight.\n\nConclusionGiven health-related behaviours are often cited as risk-factors for poor mental health, our findings suggest relationships between these factors might be more complex and dynamic in nature than currently understood. Striking increases in mental health difficulties, BMI and poor sleep related behaviours highlight an increasing public health challenge.

epidemiology↗
bioRxiv2018

Post-Hurricane Vital Statistics Expose Fragility of Puerto Rico’s Health System

ImportanceHurricane Maria made landfall in Puerto Rico on September 20, 2017. As recently as May of this year (2018), the official death count was 64. After a study describing a household survey reported a much higher death count estimate, as well as evidence of population displacement, extensive loss of services, and a prolonged death rate the government released death registry data. These newly released data will permit a better understanding of the effects of this hurricane.\n\nObjectiveProvide a detailed description of the effects on mortality of Hurricane Maria and compare to other hurricanes.\n\nDesignWe fit a statistical model to mortality data that accounts for seasonal and non-hurricane related yearly effects. We then estimated the deviation from the expected death rate as a function of time.\n\nSettingWe fit this model to 1985-2018 Puerto Rico daily data, which includes the dates of hurricanes Hugo, Georges, and Maria, 2015-2018 Florida daily data, which includes the dates of Hurricane Irma, 2002-2004 Louisiana monthly data, which includes the date of Hurricane Katrina, and 2000-2016 New Jersey monthly data, which includes the date of Hurricane Sandy.\n\nResultsWe find a prolonged increase in death rate after Maria and Katrina, lasting at least 207 and 125 days, resulting in excess deaths estimates of 3,400 (95% CI, 3,100-3,700), and 1,800 (95% CI, 1,600-2100) respectively, showing that Maria had a more long term damaging impact. Surprisingly, we also find that in 1998, Georges had a comparable impact to Katrinas with a prolonged increase of 106 days resulting in 1,400 (95% CI, 1,200-1,700) excess deaths. For Hurricane Maria, we find sharp increases in a small number of causes of deaths, including diseases of the circulatory, endocrine and respiratory system, as well as bacterial infections and suicides.\n\nConclusion and RelevanceOur analysis suggests that since at least 1998, Puerto Ricos health system has been in a precarious state. Without a substantial intervention, it appears that if hit with another strong hurricane, Puerto Ricans will suffer the unnecessary death of hundreds of its citizens.\n\nKey PointsQuestion: How does the effect of Hurricane Maria on mortality in Puerto Rico compare to the effect of other hurricanes in Puerto Rico and other United States jurisdictions?\n\nFindings: We estimate about 3,000 excess deaths after Maria, a higher toll than Katrina. Only other comparable effect was after Georges, also in Puerto Rico. For Georges and Maria, we observe a prolonged death rate increase of more than 10% lasting several months. The causes of death that increased after Maria are consistent with a collapsed health system\n\nMeaning: Puerto Ricos health system does not appear to be ready to withstand another strong hurricane.

epidemiology↗
bioRxiv2018

Different analysis methods of Scottish and English child physical activity data explain the majority of the difference between the national prevalence estimates

BackgroundThe percentage of children in Scotland and England meeting the aerobic physical activity recommendation differ greatly according to the estimates derived from the respective national health surveys. The Scottish Health Survey (SHeS) usually estimates that over 70% meet the guidelines; Health Survey for England (HSE) estimates are usually below 25%. It is plausible that these differences originate from different analysis methods. The HSE monitor the percentage of children that undertake 60 minutes of moderate-to-vigorous physical activity on each day of the week ( the daily minimum method (DMM)). The SHeS monitor the proportion that undertake at least seven sessions of moderate-to-vigorous physical activity, with an average daily duration over 60 minutes ( the average method (WAM)). We aimed to establish how great an influence this difference in analysis methods has on the prevalence estimates.\n\nMethodsPhysical activity data from 5-15 year olds in the 2015 HSE and SHeS were reanalysed (weighted n=3840 and 965, respectively). Two comparable pairs of estimates were derived: a DMM and WAM estimate from the HSE not including travel to/from school, and WAM estimates from the HSE and the SHeS including travel to/from school. It is not possible to calculate a DMM estimate from the SHeS due to the way the questions are asked. Results were presented for the total samples, and by sex and age sub-groups.\n\nResultsThe HSE WAM estimate was 31.7 (95% CI: 30.2-33.3) percentage points higher than the DMM estimate (54.3% (95% CI: 52.6-56.0) and 22.6% (95% CI: 21.2-24.1) respectively). The magnitude of this difference differed by age group but not sex. When comparable WAM estimates were derived from the SHeS and the HSE, the SHeS was 11.8 percentage points higher (73.6% (95% CI: 69.8-77.1) and 61.8% (95% CI: 60.2-63.5) respectively). The magnitude of this difference differed by age group and sex.\n\nConclusionsThe results indicate that the difference in the analysis method explains the majority (approximately 30 percentage points) of the difference in the child physical activity prevalence estimates between Scotland and England. These results will help those involved in national surveillance to determine how to increase comparability between the U.K. home nations.

epidemiology↗
bioRxiv2018

The costs of misdiagnosed asthma in a longitudinal study of the general population

ObjectivesA current diagnosis of asthma cannot be objectively confirmed in many patients with physician-diagnosed asthma. Estimates of resource use in overdiagnosed cases of asthma are necessary to measure the burden of overdiagnosis and evaluate strategies to reduce this burden. We assessed the difference in asthma-related healthcare resource use between patients with a confirmed asthma diagnosis and those with asthma ruled out.\n\nDesignPopulation-based prospective cohort study.\n\nSettingParticipants were recruited through random-digit dialling of both landlines and mobile phones in BC, Canada.\n\nParticipantsWe included 345 individuals [≥]12 years of age with a self-reported physician diagnosis of asthma which was confirmed by a bronchodilator reversibility or methacholine challenge test at the end of the 12-month follow-up.\n\nPrimary and secondary outcome measuresSelf-reported annual asthma-related direct healthcare costs (2017 Canadian dollars), outpatient physician visits, and medication use from the Canadian healthcare system perspective.\n\nResultsAsthma was ruled out in 86 (24.9%) participants. Average annual asthma-related direct healthcare costs for participants with confirmed asthma were $497.9 (SD $677.9), and $307.7 (SD $424.1) for participants with asthma ruled out. In the adjusted analyses, a confirmed diagnosis was associated with higher direct healthcare costs (Relative Ratio [RR]=1.60, 95%CI 1.14-2.22), increased rate of specialist visits (RR=2.41, 95%CI 1.05-5.40) and reliever medication use (RR=1.62, 95%CI 1.09-2.35), but not primary care physician visits (p=0.10) or controller medication use (p=0.11).\n\nConclusionsA quarter of individuals with a physician diagnosis of asthma did not have asthma after objective re-evaluation. These participants still consumed a significant amount of asthma-related healthcare resources. The population-level economic burden of asthma overdiagnosis could be substantial.\n\nStrengths and limitations of this studyO_LIParticipants were recruited through random sampling of the general population in the province of British Columbia.\nC_LIO_LIAsthma diagnosis was confirmed or ruled out using sequential guideline-recommended objective airway tests.\nC_LIO_LIHealthcare resource use was self-reported, potential recall bias may have led to reduced accuracy.\nC_LIO_LIThe study was unable to evaluate the indirect costs of overdiagnosis or the cost-savings from correcting the diagnosis.\nC_LIO_LIThe generalizability of the results may be limited by regional differences in medical costs and practices.\nC_LI

epidemiology↗
bioRxiv2018

The controlled direct effect of temperament at 2-3 years on cognitive and academic outcomes at 6-7 years

There is widespread interest in temperament and its impact upon cognitive and academic outcomes. Parents adjust their parenting according to their childs temperament, however, previous studies have not accounted for parenting while estimating the association between temperament and academic outcomes. We examined the controlled direct effect of temperament (2-3 years) on cognitive and academic outcomes (6-7 years) when mediation by parenting practices (4-5 years) was held constant. Participants were from the Longitudinal Study of Australian Children (n=5107). Cognitive abilities were measured by the Peabody Picture Vocabulary Test (verbal) and the Matrix Reasoning test (non-verbal). Literacy and numeracy were reported by teachers using the Academic Rating Scale. Mothers reported childrens temperament using the Short Temperament Scale for Toddlers (subscales: reactivity, approach, and persistence). Parenting practices included items about engagement in activities with children. Marginal structural models with inverse probability of treatment weights were used to estimate the controlled direct effect of temperament, when setting parenting to the mean. All temperament subscales were associated with cognitive abilities, with persistence showing the largest controlled direct effect on verbal ({beta}=0.58; 95%CI 0.27, 0.89) and non-verbal ({beta}=0.19; 0.02, 0.34) abilities. Higher persistence was associated with better literacy ({beta}=0.08; 0.03, 0.13) and numeracy ({beta}=0.08; 0.03, 0.13), and higher reactivity with lower literacy ({beta}=-0.08; -0.11, -0.05) and numeracy ({beta}=-0.07; -0.10, -0.04). There was little evidence that temperamental approach influenced literacy or numeracy. Overall, there was a small controlled direct effect of temperament on cognitive and academic outcomes after accounting for parenting and confounders.

epidemiology↗
bioRxiv2018

Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.

epidemiology↗
bioRxiv2018

Glutathione S-Transferase Genotype polymorphism and Primary Open-Angle Glaucoma in an Italian population

PurposeOxidative damage to the trabecular meshwork (TM) represents one of the pathogenic mechanisms leading to primary open angle glaucoma (POAG). Glutathione S-transferase mu 1 (GSTM1) may neutralizes reactive oxygen species protecting the TM. The present paper investigates the prevalence of GSTM1 null genotype in an Italian population, and its association with POAG treated either medically or surgically.\n\nMethodsIn a case-control study, the GSTM1 genotype was identified in POAGs and controls. The POAGs patients were divided in two groups: medical POAGs and surgical POAGS. Medical POAGs consisted of patients with a well-controlled intraocular pressure (IOP) by IOP-lowering medications and a stable visual field (VF). Patients with an uncontrolled IOP and a progressing VF that were submitted to incisional surgery formed the surgical POAGs group.\n\nResultsWe enrolled 104 medical POAGs, 158 surgical POAGs and 263 Controls. No significative differences between the groups existed regarding age and gender (p=0.275 and p=0.950, respectively). All the enrolled subjects were Caucasian of Italian descents. The GSTM1 null genotype was identified in 57 (45.2%) medical POAGs, 91 (57.6%) surgical POAGs and, 119 (45.3%) controls (p=0.033). The association between medical POAG and GSTM1 null status was non-significant (OR= 1.44, 95% IC = 0.86 to 2.39) whereas the association was significant for surgical POAGs (OR= 2.01, 95% IC= 1.26 to 3.21)\n\nConclusionsOur results showed an association between the GSTM1 null genotype and glaucoma that require surgery in an Italian population. GSTM1 null genotype detection may help to identify high-risk glaucoma patients that require a closer follow-up and a more aggressive treatments.

epidemiology↗
bioRxiv2018

Close proximity interactions support transmission of ESBL-K. pneumoniae but not ESBL-E. coli in healthcare settings

Antibiotic-resistance of hospital-acquired infections is a major public health issue. The worldwide emergence and diffusion of extended-spectrum {beta}-lactamase (ESBL)-producing Enterobacteriaceae, including Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP), is of particular concern. Preventing their nosocomial spread requires understanding their transmission. Using Close Proximity Interactions (CPIs), measured by wearable sensors, and weekly ESBL-EC- and ESBL-KP-carriage data, we traced their possible transmission paths among 329 patients in a 200-bed long-term care facility over 4 months. Based on phenotypically defined resistance profiles to 12 antibiotics, new bacterial acquisitions were tracked. Extending a previously proposed statistical method, the CPI networks ability to support observed incident colonization episodes of ESBL-EC and ESBL-KP was tested. Finally, mathematical modeling based on our findings assessed the effect of several infection-control measures. A potential infector was identified in the CPI network for 80% (16/20) of ESBL-KP acquisition episodes. The lengths of CPI paths between ESBL-KP incident cases and their potential infectors were shorter than predicted by chance (P = 0.02), indicating that CPI-network relationships were consistent with dissemination. Potential ESBL-EC infectors were identified for 54% (19/35) of the acquisitions, with longer-than-expected lengths of CPI paths. These contrasting results yielded differing impacts of infection control scenarios, with contact reduction interventions proving less effective for ESBL-EC than for ESBL-KP. These results highlight the widely variable transmission patterns among ESBL-producing Enterobacteriaceae species CPI networks supported ESBL-KP, but not ESBL-EC spread. These outcomes could help design more specific surveillance and control strategies to prevent in-hospital Enterobacteriaceae dissemination.\n\nAuthor summaryTracing extended-spectrum {beta}-lactamase (ESBL) dissemination in hospitals is an important step in the fight against the spread of multi-drug resistant bacteria. Indeed, understanding ESBL spreading dynamics will help identify efficient control interventions. In the i-Bird study, patients and hospital staff from a French long-term care facility in France carried a wearable sensor to capture their interactions at less than 1.5 meters, every 30 seconds over a 4-month period. Every week, patients were also swabbed to detect carriage of ESBL-producing Enterobacteriaceae. Based on the analysis of these longitudinal data, this study shows that ESBL-producing Klebsiella pneumoniae (ESBL-KP) mostly spreads during close-proximity interactions between individuals, while this is not the case for ESBL-producing Escherichia coli (ESBL-EC), suggesting that ESBL-KP but not ESBL-EC may be controlled by contact reduction interventions.

epidemiology↗
bioRxiv2018

Increasing Rates of Diagnosis, Substantial Co-occurrence, and Variable Treatment Patterns of Eosinophilic Gastritis, Gastroenteritis and Colitis Based on 10 Year Data Across a Multi-Center Consortium

Financial Support and AcknowledgementsSupport for this project was provided through a research training grant as part of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) (U54 AI117804). CEGIR is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC. This project also received support from NIH T32 DK007634 (CCR).\n\nAuthor DisclosersPatricia Fulkerson: Grant funding from the NIH; Consultant for Genentech, Inc; Research support from Knopp Biosciences, LLC.\n\nGary Falk: Research support from Shire, Celgene, Adare, Regeneron. Consulting for Shire\n\nJonathan M. Spergel: Consultant for Regeneron, DBV Technology, Kaleo; Grant funding from DBV Technology, Aimmune Therapeutics, Food Allergy Research Education; Royalties from UpToDate\n\nNirmala Gonsalves: Royalties from UpToDate; Advisory board for Allakos\n\nSandeep K Gupta: Consultant for Alkalos, Abbott, QOL, Receptos; research support from Shire\n\nGlenn Furuta: Founder of EnteroTrack; Consultant for Shire; Royalties from UpToDate\n\nMarc E. Rothenberg: Consultant for Pulm One, Spoon Guru, ClostraBio, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first four listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. M.E.R. is an inventor of patents owned by Cincinnati Childrens.\n\nEvan Dellon: Consultant for Adare, Allakos, Alivio, Banner, Celgen/Receptos, Enumeral, GSK, Regeneron, Shire; Research funding from Adare, Celegene/Receptos, Miraca, Meritage, Nutricia, Regeneron, Shire, Educational grant from Banner, Holoclara\n\nStudy HighlightsO_ST_ABSWhat is current knowledge?C_ST_ABSO_LIEosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), gastroenteritis (EGE), and colitis (EC).\nC_LIO_LINon-EoE EGIDs are rare with most studies limited to case reports or review of single center experiences.\nC_LIO_LIThere are no widely established guidelines for the diagnosis of EG, EGE, or EC.\nC_LI\n\nWhat is new here?O_LIIn this multicenter study, EG, EGE, and EC were all diagnosed with increasing frequency over the past decade.\nC_LIO_LIPresenting symptoms are non-specific and do not reliably distinguish between disorders.\nC_LIO_LIThere was no male predominance and the majority of subjects had atopy.\nC_LIO_LICo-occurrence of EG, EGE, and EC diagnoses is common, seen in 41% of patients.\nC_LIO_LIThere is substantial variability between centers in initial treatment approaches.\nC_LI

epidemiology↗
bioRxiv2018

A decision-support framework to optimize border control for global outbreak mitigation

The introduction and spread of emerging infectious diseases is increasing in both prevalence and scale. Whether naturally, accidentally or maliciously introduced, the substantial uncertainty surrounding the emergence of novel viruses, specifically where they may come from and how they will spread, demands robust and quantifiably validated outbreak control policies that can be implemented in real time. This work presents a novel mathematical modeling framework that integrates both outbreak dynamics and outbreak control into a decision support tool for mitigating infectious disease pandemics that spread through passenger air travel. An ensemble of border control strategies that exploit properties of the air traffic network structure and expected outbreak behavior are proposed. A stochastic metapopulation epidemic model is developed to evaluate and rank the control strategies based on their effectiveness in reducing the spread of outbreaks. Sensitivity analyses are conducted to illustrate the robustness of the proposed control strategies across a range of outbreak scenarios, and a case study is presented for the 2009 H1N1 influenza pandemic. This study highlights the importance of strategically allocating outbreak control resources, and the results can be used to identify the most robust border control policy that can be implemented in the early stages of an outbreak.

epidemiology↗
bioRxiv2018

Overestimation of the prevalence of eosinophilic colitis with reliance on a single billing code

Eosinophilic colitis (EC) is a rare disorder characterized by eosinophilic inflammation of the colon causing diarrhea, bloody stool, nausea, constipation and abdominal pain. The Consortium for Eosinophilic Gastrointestinal Disease Research sought to undertake the first multi-center study of the EC population, but faced challenges with meeting enrollment goals that were based on initial estimates. To understand the reason for this, we performed chart review of patients with ICD codes for EC at 8 tertiary care centers. Chart review revealed that the isolated use of ICD codes overestimated EC rates in the pediatric population.

epidemiology↗
bioRxiv2018

Rates of increase of antibiotic resistance and ambient temperature in Europe: a cross-national analysis of 28 countries between 2000-2016

BackgroundWidely recognized as a major public health threat globally, the rapid increase of antibiotic resistance in bacteria could soon render our most effective method to combat infections obsolete. Factors influencing the burden of resistance in human populations remain poorly described, though temperature is known to play an important role in mechanisms at the bacterial level.\n\nMethodsWe performed an ecologic analysis of country level antibiotic resistance prevalence in 3 common bacterial pathogens across 28 countries in Europe, and used multivariable models to evaluate associations with minimum temperature and other predictors over a 17-year period (2000-2016). We quantified the effects of minimum temperature, population density, and antibiotic consumption on the rate of change of antibiotic resistance across geographies.\n\nFindingsFor three common bacterial pathogens and four classes of antibiotics, we found evidence of a long-term effect of ambient minimum temperature on rates of increase of antibiotic resistance across 28 countries in Europe between 2000-2016. Specifically, we show that across all antibiotic classes for the pathogens E. coli and K. pneumoniae, European countries with 10{degrees}C warmer ambient temperatures have experienced more rapid increases in antibiotic resistance over the 17-year period, ranging between 0.33%/year (95% CI 0.2, 0.5) and 1.2%/year (0.4, 1.9), even after accounting for recognized drivers of resistance including antibiotic consumption and population density. We found a decreasing relationship for S. aureus and methicillin of -0.4%/year (95% CI -0.7, 0.0), reflecting widespread declines in MRSA across Europe over the study period.\n\nInterpretationAmbient temperature may be an important modulator of the rate of change of antibiotic resistance. Our findings suggest that rising temperatures globally may hasten the spread of resistance and complicate efforts to mitigate it.\n\nFundingCanadian Institutes of Health Research Fellowship (D.R.M.).

epidemiology↗
bioRxiv2018

Limited marginal utility of deep sequencing for HIV drug resistance testing in the age of integrase inhibitors

HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect lower frequency alleles. However, the value added from NGS approaches to antiviral resistance testing remains to be demonstrated. We compared the variant detection capacity of NGS versus Sanger sequencing methods for resistance genotyping of 144 drug resistance tests (105 protease-reverse transcriptase tests and 39 integrase tests) submitted to our clinical virology laboratory over a four-month period in 2016 for Sanger-based HIV drug resistance testing. NGS detected all true high frequency drug resistance mutations (>20% frequency) found by Sanger sequencing, with greater accuracy in one instance of a Sanger-detected false positive. Freely available online NGS variant callers Hydra and PASeq were superior to Sanger methods for interpretations of allele linkage and automated variant calling. NGS additionally detected low frequency mutations (1-20% frequency) associated with higher levels of drug resistance in 30/105 (29%) of protease-reverse transcriptase tests and 4/39 (10%) of integrase tests. Clinical follow-up of 69 individuals for a median of 674 days found no difference in rates of virological failure between individuals with and without low frequency mutations, although rates of virological failure were higher for individuals with drug-relevant low frequency mutations. However, all 27 individuals who experienced virological failure reported poor adherence to their drug regimen during preceding follow-up time, and all 19 who subsequently improved their adherence achieved viral suppression at later time points consistent with a lack of clinical resistance. In conclusion, in a population with low antiviral resistance emergence, NGS methods detected numerous instances of minor alleles that did not result in subsequent bona fide virological failure due to antiviral resistance.\n\nImportanceGenotypic antiviral resistance testing for HIV is an essential component of the clinical microbiology and virology laboratory. Next-generation sequencing (NGS) has emerged as a powerful tool for the detection of low frequency sequence variants (allele frequencies <20%). Whether detecting these low frequency mutations in HIV contributes to improved patient health, however, remains unclear. We compared NGS to conventional Sanger sequencing for detecting resistance mutations for 144 HIV drug resistance tests submitted to our clinical virology laboratory and detected low frequency mutations in 24% of tests. Over approximately two years of follow-up for 69 patients for which we had access to electronic health records, no patients had virological failure due to antiviral resistance. Instead, virological failure was entirely explained by medication non-adherence. While larger studies are required, we suggest that detection of low frequency variants by NGS presents limited marginal clinical utility when compared to standard of care.

epidemiology↗
bioRxiv2018

Evaluating the effects of data visualisation techniques on interpretation and preference in clinical quality reports: A cross-sectional study.

ObjectiveTo evaluate the different methods of data visualisation and how it affects preference and data interpretation.\n\nDesignA cross-sectional survey, assessing interpretation and preference for four methods of data presentation, was distributed to participants.\n\nSettingMelbourne, Victoria\n\nParticipantsMembers of Prostate Cancer Outcome Registry-Victoria (PCOR-Vic) and senior hospital staff in three metropolitan Victorian hospitals.\n\nInterventionsDifferent methods of data visualisation. Mainly, funnel plots, league charts, risk adjusted sequential probability ratio test (RASPRT) charts and dashboard.\n\nMain Outcome MeasureInterpretation scores assessed capacity by participants to identify outliers and poor performers. Preference was based on a 9-point Likert-scale (0 - 9).\n\nResultsIn total, 113 participants responded to the online survey (16/58 urologists and 97/297 senior hospital staff, response rate 32%). Respondents reported that funnel plots were easier to interpret compared to league charts (mean interpretability score difference of 28% (95% CI: 19.2% - 37.0%, P<0.0001). Predictors of worse interpretability of charts in the adjusted model were being a hospital executive compared to a urologist (coefficient= -2.50, 95% CI = -3.82, - 1.18, P<0.01) and having no statistical training compared to those with statistical training (coefficient = -1.71, 95% CI=-2.85, -0.58, P=0.003). Participants preferred funnel plots and dashboards compared to league charts and RASPRT charts (median score 7/9 vs 5/9), and preferred charts which were traffic-light coloured versus greyscale charts (43/60 (71.6%) vs 17/60 (28.3%)).\n\nConclusionWhen developing reports for clinicians and hospitals, consideration should be given to preference of end-users and ability of groups to interpret the graphs.

epidemiology↗
bioRxiv2018

Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population.

BackgroundInfluenza vaccines are important for prevention of influenza-associated hospitalization. Assessments of serologic correlates of protection can support interpretation of influenza vaccine effectiveness evaluations in hospitalized populations.\n\nMethodsSerum specimens collected at admission from adults hospitalized for treatment of acute respiratory illnesses during two influenza seasons were tested in hemagglutination-inhibition (HAI) and neuraminidase-inhibition (NAI) assays. We evaluated the suitability of these specimens as proxies for pre-infection immune status, and measured associations between antibody titers and influenza vaccination and infection\n\nResultsSpecimens were collected within 3 days of illness onset from 65% of participants; geometric mean titers (GMTs) did not vary by day of collection. In both seasons, vaccinated participants had higher HAI and NAI GMTs than unvaccinated participants. HAI titers against the 2014-2015 A(H3N2) vaccine strain did not correlate with protection from infection with antigenically-drifted A(H3N2) viruses that circulated that season. In contrast, higher HAI titers against the A(H1N1)pdm09 vaccine strain were associated with reduced odds of A(H1N1)pdm09 infection in 2015-2016.\n\nConclusionsSerum collected after hospital admission can be used to assess correlates of protection against influenza infection. Broader implementation of similar studies would provide an opportunity to understand the successes and shortcomings of current influenza vaccines.

epidemiology↗
bioRxiv2018

Quantifying miscarriage sex bias in England and Wales, 1993-2017

Given an equal sex ratio at conception, we can only explain the excess of human males at birth by greater loss of females during pregnancy. I propose that the bias against females during human development is the result of a greater degree of genetic and metabolic \"differentness\" between female embryos and maternal tissues than for similarly aged males, and that successful implantation and placentation represents a threshold dichotomy, where the acceptance threshold shifts depending on maternal condition, especially stress. Right and left ovaries are not equal, and neither are the eggs and follicular fluid that they produce, and I further hypothesise that during times of stress, the implantation threshold is shifted sufficiently to favour survival of females, most likely those originating from the right ovary, and that this, rather than simply a greater loss of males, explains at least some of the variability in the human sex ratio at birth.

epidemiology↗