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bioRxiv2018

Retention of adults from fishing communities in an HIV vaccine preparedness study in Masaka, Uganda

IntroductionPeople living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda.\n\nMethodsHIV high risk, sero-negative adults (18-49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for: screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models.\n\nResultsA total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years. Dropout was associated with being female (aRR =1.56, 95% confidence interval [CI] 1.12-2.18), age, being 18-24 years (aRR=1.64; 95% CI 1.03-2.60), 25-34 years (aRR=1.63; 95% CI 1.04-2.55); having no education (aRR=2.02; 95% CI: 1.23-3.31); living in the community for less than one year (aRR=2.22; 95% CI: 1.46-3.38) or 1-5 years (aRR=1.68; 95% CI: 1.16-2.45) and occupation.\n\nConclusionsIt is possible to recruit and retain individuals from fishing communities, however, intensified participant tracing may be necessary in a vaccine trial to keep in follow up female, young, less educated, those in mobile occupations and new residents.

epidemiology↗

bioRxiv2018

A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

IMPORTANCEGenetic diseases are a leading cause of childhood mortality. Whole genome sequencing (WGS) and whole exome sequencing (WES) are relatively new methods for diagnosing genetic diseases.\n\nOBJECTIVESCompare the diagnostic sensitivity (rate of causative, pathogenic or likely pathogenic genotypes in known disease genes) and rate of clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and chromosomal microarrays (CMA) in children with suspected genetic diseases.\n\nDATA SOURCES AND STUDY SELECTIONSystematic review of the literature (January 2011 - August 2017) for studies of diagnostic sensitivity and/or clinical utility of WGS, WES, and/or CMA in children with suspected genetic diseases. 2% of identified studies met selection criteria.\n\nDATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently following MOOSE/PRISMA guidelines.\n\nMAIN OUTCOMES AND MEASURESPooled rates and 95% Cl were estimated with a random-effects model. Metaanalysis of the rate of diagnosis was based on test type, family structure, and site of testing.\n\nRESULTSIn 36 observational series and one randomized control trial, comprising 20,068 children, the diagnostic sensitivity of WGS (0.41, 95% Cl 0.34-0.48, I2=44%) and WES (0.35, 95% Cl 0.31-0.39, I2=85%) were qualitatively greater than CMA (0.10, 95% Cl 0.08-0.12, I2=81%). Subgroup meta-analyses showed that the diagnostic sensitivity of WGS was significantly greater than CMA in studies published in 2017 (P<.0001, I2=13% and I2=40%, respectively), and the diagnostic sensitivity of WES was significantly greater than CMA in studies featuring within-cohort comparisons (P<001, I2=36%). Evidence for a significant difference in the diagnostic sensitivity of WGS and WES was lacking. In studies featuring within-cohort comparisons of singleton and trio WGS/WES, the likelihood of diagnosis was significantly greater for trios (odds ratio 2.04, 95% Cl 1.62-2.56, I2=12%; P<.0001). The diagnostic sensitivity of WGS/WES with hospital-based interpretation (0.41, 95% Cl 0.38-0.45, I2=50%) was qualitatively higher than that of reference laboratories (0.28, 95% Cl 0.24-0.32, I2=81%); this difference was significant in meta-analysis of studies published in 2017 (P=.004, I2=34% and I2=26%, respectively). The rates of clinical utility of WGS (0.27, 95% Cl 0.17-0.40, I2=54%) and WES (0.18, 95% Cl 0.13-0.24, I2-77%) were higher than CMA (0.06, 95% Cl 0.05-0.07, I2=42%); this difference was significant in meta-analysis of WGS vs CMA (P<.0001).\n\nCONCLUSIONS AND RELEVANCEIn children with suspected genetic diseases, the diagnostic sensitivity and rate of clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic sensitivity were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the relative diagnostic sensitivity and clinical utility of different genome tests in children with suspected genetic diseases?\n\nFindingsWhole genome sequencing had greater diagnostic sensitivity and clinical utility than chromosomal microarrays. Testing parent-child trios had greater diagnostic sensitivity than proband singletons. Hospital-based testing had greater diagnostic sensitivity than reference laboratories.\n\nMeaningTrio genomic sequencing is the most sensitive diagnostic test for children with suspected genetic diseases.

genomics↗

bioRxiv2018

How molecular mechanisms of resistance affect resistance evolution

Combatting antibiotic resistance will require both new antibiotics and strategies to preserve the effectiveness of existing drugs. Both approaches would benefit from predicting optimal dosing of antibiotics based on drug-target binding parameters that can be measured early in drug development and that can change when bacteria become resistant. This would avoid the currently frequently employed trial-and-error approaches and might reduce the number of antibiotic candidates that fail late in drug development.\n\nHere, we describe a computational model (COMBAT-COmputational Model of Bacterial Antibiotic Target-binding) that leverages accessible biochemical parameters to quantitatively predict antibiotic dose-response relationships. We validate our model with MICs of a range of quinolone antibiotics in clinical isolates demonstrating that antibiotic efficacy can be predicted from drug-target binding (R2 > 0.9). To further challenge our approach, we do not only predict antibiotic efficacy from biochemical parameters, but also do the reverse: estimate the magnitude of changes in drug-target binding based on antibiotic dose-response curves. We experimentally demonstrate that changes in drug-target binding can be predicted from antibiotic dose-response curves with 92-94 % accuracy by exposing bacteria overexpressing target molecules to ciprofloxacin. To test the generality of COMBAT, we apply it to a different antibiotic class, the beta-lactam ampicillin, and can again predict binding parameters from dose-response curves with 90 % accuracy. We then apply COMBAT to predict antibiotic concentrations that can select for resistance due to novel resistance mutations.\n\nOur goal here is dual: First, we address a fundamental biological question and demonstrate that drug-target binding determines bacterial response to antibiotics, although antibiotic action involves many additional effects downstream of drug-target binding. Second, we create a tool that can help accelerate drug development by predicting optimal dosing and preserve the efficacy of existing antibiotics by predicting optimal treatment for possible resistant mutants.

biochemistry↗

bioRxiv2016

Case Report: Aggressive Tibial Pseudarthrosis as Primary Symptom in Infant with Neurofibromatosis

Neurofibromatosis (NF1) is a rare genetic neurologic disorder with over 30 distinct clinical manifestations, the top 3 of which include cafe-au-lait spotting, benign tumors and abnormal freckling. Pseudarthrosis (PA), also known as a \"false joint,\" is a rare subset of NF1 symptomology, characterized by bone fractures and nonunion caused by severe bowing of long bones. To date, it is invariably reported as secondary to NF1, commonly at 24 months of age. Here we describe a 4-month old infant who presented with PA as primary symptom, and in absence of an NF1 first-degree relative. Initial manifestation was guarding of the leg and increased irritability upon palpation of the knee, subsequent to light playful jostling. Physician examination revealed gross anterolateral bowing of the left leg. Radiography confirmed tibia-fibula bowing and pathologic transverse fracture at tibia diaphysis, characteristic of PA. Cafe-au-lait spots developed at 6 months subsequent to PA, but with number and size well below the National Institutes of Health criteria for NF1 diagnosis. At 14 months, exome sequencing established definitive NF1 diagnosis. Treatment involved PA takedown surgery. Although healing was seen after 2 months, complications emerged by 6 months. This case suggests that for primary PA without clear etiology, first-contact and consulting physicians should pay careful attention and be vigilant to timing of clinical onset and severity. Early, severe primary PA warrants accelerated NF1 exome sequencing, suggesting expansion of existing federal guidelines may be necessary to improve detection and prognosis of this rare, debilitating but readily managed condition.\n\nFinancial DisclosureThe authors have no financial relationships relevant to this article to disclose\n\nConflict of InterestThe authors have no conflicts of interest to disclose\n\nClinical Trial RegistrationNA

Genetics↗

bioRxiv2016

The impact of the newly licensed dengue vaccine in endemic countries

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

Epidemiology↗

bioRxiv2017

ERAASR: An algorithm for removing electrical stimulation artifacts from multielectrode array recordings

Electrical stimulation is a widely used and effective tool in systems neuroscience, neural prosthetics, and clinical neurostimulation. However, electrical artifacts evoked by stimulation significantly complicate the detection of spiking activity on nearby recording electrodes. Here, we present ERAASR: an algorithm for Estimation and Removal of Artifacts on Arrays via Sequential principal components Regression. This approach leverages the similar structure of artifact transients, but not spiking activity, across simultaneously recorded channels on the array, across pulses within a train, and across trials. The effectiveness of the algorithm is demonstrated in macaque dorsal premotor cortex using acute linear multielectrode array recordings and single electrode stimulation. Large electrical artifacts appeared on all channels during stimulation. After application of ERAASR, the cleaned signals were quiescent on channels with no spontaneous spiking activity, whereas spontaneously active channels exhibited evoked spikes which closely resembled spontaneously occurring spiking waveforms. The ERAASR algorithm requires no special hardware and comprises sequential application of straightforward linear methods with intuitive parameters. Enabling simultaneous electrical stimulation and multielectrode array recording can help elucidate the causal links between neural activity and cognitive functions and enable the design and implementation of novel sensory protheses.

neuroscience↗

bioRxiv2018

Characteristic impairments of goal-directed and habitual control in bulimia nervosa

The relationship between clinical eating disorder symptom severity and balance of model-based (MB) and model-free (MF) control is unclear, and these traits predictive capacity is untested in this population. In 25 healthy controls (HCs), 25 subjects with binge eating disorder (BED), and 25 subjects with bulimia nervosa (BN), we show an inverse relationship between symptom severity and MB (though not MF) control. However, trial-by-trial behavioural data discriminated BN from other groups (area under receiver operating characteristic curve of 0.78; 95% CI=0.64-0.92) based primarily on impaired MF control. Our data--including analyses of reaction time and theory-driven computational modeling--support the hypothesis that among pathological binge eating groups, BN may be characterized by impaired value function learning. Our results suggest that trial-by-trial analysis of behavioural data may provide unique insights into the BN phenotype, which may thus be computationally distinct from the related disorder of BED and the HC state.

neuroscience↗

bioRxiv2018

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

BackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.\n\nMethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.\n\nResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).\n\nConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

genetics↗

bioRxiv2017

Selective attention modulates surface filling-in

The visual system is required to compute objects from partial image structure so that figures can be segmented from their backgrounds. Although early clinical, behavioral, and modeling data suggested that such computations are performed pre-attentively, recent neurophysiological evidence suggests that surface filling-in is influenced by attention. In the present study we developed a variant of the classical Kanizsa illusory triangle to investigate whether voluntary attention modulates perceptual filling-in. Our figure consists of \"pacmen\" positioned at the tips of an illusory 6-point star and alternating in polarity such that two illusory triangles are implied to compete with one another within the figure. On each trial, observers were cued to attend to only one triangle, and then compared its lightness with a matching texture-defined triangle. We found that perceived lightness of the illusory shape depended on the polarity of pacmen framing the attended triangle, although the magnitude of this effect was weaker than when all inducers were of the same polarity. Our findings thus reveal that voluntary attention can influence lightness filling-in, and provide important data linking neurophysiological effects to phenomenology.

neuroscience↗

bioRxiv2017

The crossmodal congruency effect, a tool incorporation metric, suffers from a learning effect with repeated exposures

The incorporation of feedback into a persons body schema is well established. The crossmodal congruency effect (CCE) task is used to objectively quantify incorporation without being susceptible to experimenter biases. This visual-tactile interference task is used to calculate the CCE score as a difference in response time for incongruent and congruent trials. Here we show that this metric is susceptible to a learning effect that causes attenuation of the CCE score due to repeated task exposure sessions. We demonstrate that this learning effect is persistent, even after a 6 month hiatus in testing. Two mitigation strategies are proposed: 1. Only use CCE scores that are taken after learning has stabilized, or 2. Use a modified CCE protocol that decreases the task exposure time. We show that the modified and shortened CCE protocol, which may be required to meet time or logistical constraints in laboratory or clinical settings, reduced the impact of the learning effect on CCE results. Importantly, the CCE scores from the modified protocol were not significantly more variable than results obtained with the original protocol. This study highlights the importance of considering exposure time to the CCE task when designing experiments and suggests two mitigation strategies to improve the utility of this psychophysical assessment.

neuroscience↗

bioRxiv2018

Antibody-based vaccine for TB: pre-clinical validation in horse foals challenged with the TB-related pathogen Rhodococcus equi

Immune correlates for protection against Mycobacterium tuberculosis (Mtb) infection and other intracellular pathogens are largely undetermined. Whether there is a role for antibody-mediated immunity is controversial. Rhodococcus equi is an intracellular pathogen causing severe pneumonia in young horse foals, eliciting a disease with many similarities to TB including intracellular residence, formation of granulomas and induction of severe respiratory distress. No purified vaccine antigens exist for R. equi or Mtb infections. Both express the microbial surface polysaccharide antigen poly-N-acetyl glucosamine (PNAG). Vaccination of pregnant mares with a synthetic PNAG oligosaccharide conjugated to tetanus toxoid elicited antibody that transferred to foals via colostrum and provided nearly complete protection against R. equi pneumonia in a randomized, controlled, blinded challenge trial. Infusion of PNAG-hyperimmune plasma protected 100% of foals against R. equi pneumonia. Vaccination induced opsonic antibodies that killed extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms was dependent on antibody recognition of surface expression of PNAG on infected macrophages, complement deposition and PMN-assisted lysis of infected macrophages. Protection also correlated with PBMC release of interferon-{gamma} in response to PNAG. Antibody-mediated opsonic killing and interferon-{gamma} release in response to PNAG may protect against disease caused by intracellular bacterial pathogens.

immunology↗

bioRxiv2018

Can machine learning assess trunk alignment directly from raw video?

BackgroundThe Segmental Assessment of Trunk Control (SATCo) evaluates sitting control at seven separate trunk segments, making a judgement based on their position in space relative to a defined, aligned posture. SATCo is in regular clinical and research use and is a Recommended Instrument for Cerebral Palsy and Spinal Cord Injury-Paediatric by The National Institute of Neurological Disorders and Stroke (US). However, SATCo remains a subjective assessment.\n\nResearch questionThis study tests the feasibility of providing an objective, automated identification of frames containing the aligned, reference trunk posture using deep convolutional neural network (DCNN) analysis of raw high definition and depth (HD+D) images.\n\nMethodsA SATCo was conducted on sixteen healthy male adults and recorded using a Kinect V2. For each of seven segments tested, two different trials were collected (control and no-control) to simulate a range of alignment configurations. For all images, classification of alignment obtained from a trained and validated DCNN was compared to expert clinicians labelling.\n\nResultsUsing leave-one-out testing, at the optimal operating threshold, the DCNN correctly classified individual images (alignment v misaligned) with average precision 92.7{+/-}16% (mean{+/-}SD).\n\nSignificanceThese results show for the first time, automation of a key component of the SATCo test, namely identification of aligned trunk posture directly from raw images (HD+D). This demonstrates the potential of machine learning to provide a fully automated, objective SATCo test to enhance assessment of trunk control in children and adults for research and treatment of various conditions including neurodisability and stroke.

bioengineering↗

bioRxiv2017

A cautionary tale on using tumour growth rate to predict survival

A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. We found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial we found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

cancer biology↗

bioRxiv2018

Improving the diagnostic yield of exome-sequencing, by predicting gene-phenotype associations using large-scale gene expression analysis

Clinical interpretation of exome and genome sequencing data remains challenging and time consuming, with many variants with unknown effects found in genes with unknown functions. Automated prioritization of these variants can improve the speed of current diagnostics and identify previously unknown disease genes. Here, we used 31,499 RNA-seq samples to predict the phenotypic consequences of variants in genes. We developed GeneNetwork Assisted Diagnostic Optimization (GADO), a tool that uses these predictions in combination with a patients phenotype, denoted using HPO terms, to prioritize identified variants and ease interpretation. GADO is unique because it does not rely on existing knowledge of a gene and can therefore prioritize variants missed by tools that rely on existing annotations or pathway membership. In a validation trial on patients with a known genetic diagnosis, GADO prioritized the causative gene within the top 3 for 41% of the cases. Applying GADO to a cohort of 38 patients without genetic diagnosis, yielded new candidate genes for seven cases. Our results highlight the added value of GADO (www.genenetwork.nl) for increasing diagnostic yield and for implicating previously unknown disease-causing genes.

genetics↗

bioRxiv2018

Judgments of other bias in Cochrane systematic reviews of interventions are highly inconsistent and thus hindering use and comparability of evidence

BackgroundClinical decisions are made based on Cochrane systematic reviews (CSRs), but implementation of results of evidence syntheses such as CSRs is problematic if the evidence is not prepared consistently. All systematic reviews should assess risk of bias (RoB) in included studies, and in CSRs this is done by using Cochrane RoB tool. However, the tool is not necessarily applied according to the instructions. In this study we aimed to analyze types and judgments of other bias in the RoB tool in CSRs of interventions.\n\nMethodsWe analyzed CSRs that included randomized controlled trials (RCTs) and extracted data regarding other bias from the RoB table and accompanying support for the judgment. We categorized different types of other bias.\n\nResultsWe analyzed 768 CSRs that included 11369 RCTs. There were 602 (78%) CSRs that had other bias domain in the RoB tool, and they included a total of 7811 RCTs. In the RoB table of 337 CSRs for at least one of the included trials it was indicated that no other bias was found and supporting explanations were inconsistently judged as low, unclear or high RoB. In the 524 CSRs that described various sources of other bias there were 5762 individual types of explanations which we categorized into 31 groups. The judgments of the same supporting explanations were highly inconsistent. Furthermore, we found numerous other inconsistencies in reporting of sources of other bias in CSRs.\n\nConclusionCochrane authors mention a wide range of sources of other bias in the RoB tool and they inconsistently judge the same supporting explanations. Inconsistency in appraising risk of other bias hinders reliability and comparability of Cochrane systematic reviews. Furthermore, discrepant and erroneous judgments of bias in evidence synthesis will inevitably hinder implementation of evidence in routine clinical practice and reduce confidence of practitioners in otherwise trustworthy sources of information.

epidemiology↗

bioRxiv2015

Incomplete protection against dengue virus type 2 re-infection in Peru

Background. Nearly half of the worlds population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010-2011, 15 years after the first outbreak of DENV-2 in the region. Methodology/Principal Findings. We estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010-2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0% -- 65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1 - 17.7). Conclusions/Significance. Our data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics. Author SummaryHomotypic immunity against DENV infection has been assumed to be complete and lifelong, and to our knowledge, instances of homologous DENV re-infection have not been rigorously documented. However, few long-term studies have been conducted in such a way that homologous re-infection could be observed, if it did in fact occur. Our study provides evidence that homologous re-infection may occur in certain circumstances. We draw from data collected during a 2010-2011 DENV-2 epidemic in northeastern Peru, 15 years after the initial DENV-2 outbreak in the region. This finding has significant implications for our understanding of dengue epidemiology and for dengue vaccine formulation, which may need to consider multiple genotypes of each serotype. Data from other long-term dengue epidemiology studies should be analyzed to determine of homologous re-infection is a more widespread phenomenon.

Immunology↗

bioRxiv2017

A comparison of tests for quantifying sensory eye dominance

Clinicians rely heavily on stereoacuity to measure binocular visual function, but stereo-vision represents only one aspect of binocularity. Lab-based tests of sensory eye dominance (SED) are commonplace, but have not been translated to wider clinical practice. Here we compare several methods of quantifying SED in a format suitable for clinical use. We tested 30 participants with ostensibly normal vision on 8 tests. Seven tests (#1-7) were designed to quantify SED in the form of an interocular balance-point (BP). In tests #1-6, we estimated a contrast-BP, the interocular difference in contrast required for observers to be equally likely to base their judgement on either eye, whereas in test #7 we measured binocular rivalry (interocular ratio of sensory dominance duration). We compare test-retest reliability (intra-observer consistency) and test-validity (inter-observer discriminatory power) and compare BP to stereoacuity (test #8). The test that best preserved inter-observer differences in contrast balance while maintaining good test-retest reliability was a polarity judgement using superimposed opposite-contrast polarity same-identity optotypes. A reliable and valid measure of SED can be obtained rapidly (20 trials) using a simple contrast-polarity judgement. Tests that use polarity-rivalrous stimuli elicit more reliable judgments than those that do not.\n\nSignificance StatementAlthough sensory eye dominance is central to understanding normal and disordered binocular vision, there is currently no consensus as to the best way to measure it. Here we compare several candidate measures of sensory eye dominance and conclude that a reliable measure of SED can be achieved rapidly using a judgement of stimulus contrast-polarity.

neuroscience↗

bioRxiv2016

Investigating side effect modules in the interactome and their use in drug adverse effect discovery

One of the biggest challenges in drug development is increasing costs of bringing new drugs to the market. Many candidate drugs fail during phase II and III trials due to unexpected side effects and experimental methods remain cost ineffective for large scale discovery of adverse effects. Alternatively, computational methods are used to characterize drug side effects, but they often rely on training predictors based on drug and side effect similarity. Moreover, these methods are typically tailored to the underlying data set and provide little mechanistic insights on the predicted associations. In this study, we investigate the role of network topology in explaining observed side effects of drugs. We find that drug targets are closer in the interactome to the proteins inducing the known side effects of the drug compared to the proteins associated with the rest of the side effects. We show that the interactome based proximity can be used to identify side effects and we highlight a use case in which interactome-based side effect prediction can give insights on drug side effects observed in the clinic.

systems biology↗