Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 53 Records) |
Query Trace: Campo P[original query] |
---|
Evaluation of viral heterogeneity using next-generation sequencing, end-point limiting-dilution and mass spectrometry.
Dimitrova Z , Campo DS , Ramachandran S , Vaughan G , Ganova-Raeva L , Lin Y , Forbi JC , Xia G , Skums P , Pearlman B , Khudyakov Y . In Silico Biol 2011 11 183-92 Hepatitis C Virus sequence studies mainly focus on the viral amplicon containing the Hypervariable region 1 (HVR1) to obtain a sample of sequences from which several population genetics parameters can be calculated. Recent advances in sequencing methods allow for analyzing an unprecedented number of viral variants from infected patients and present a novel opportunity for understanding viral evolution, drug resistance and immune escape. In the present paper, we compared three recent technologies for amplicon analysis: (i) Next-Generation Sequencing; (ii) Clonal sequencing using End-point Limiting-dilution for isolation of individual sequence variants followed by Real-Time PCR and sequencing; and (iii) Mass spectrometry of base-specific cleavage reactions of a target sequence. These three technologies were used to assess intra-host diversity and inter-host genetic relatedness in HVR1 amplicons obtained from 38 patients (subgenotypes 1a and 1b). Assessments of intra-host diversity varied greatly between sequence-based and mass-spectrometry-based data. However, assessments of inter-host variability by all three technologies were equally accurate in identification of genetic relatedness among viral strains. These results support the application of all three technologies for molecular epidemiology and population genetics studies. Mass spectrometry is especially promising given its high throughput, low cost and comparable results with sequence-based methods. |
Hepatitis C virus antigenic convergence.
Campo DS , Dimitrova Z , Yokosawa J , Hoang D , Perez NO , Ramachandran S , Khudyakov Y . Sci Rep 2012 2 267 Vaccine development against hepatitis C virus (HCV) is hindered by poor understanding of factors defining cross-immunoreactivity among heterogeneous epitopes. Using synthetic peptides and mouse immunization as a model, we conducted a quantitative analysis of cross-immunoreactivity among variants of the HCV hypervariable region 1 (HVR1). Analysis of 26,883 immunological reactions among pairs of peptides showed that the distribution of cross-immunoreactivity among HVR1 variants was skewed, with antibodies against a few variants reacting with all tested peptides. The HVR1 cross-immunoreactivity was accurately modeled based on amino acid sequence alone. The tested peptides were mapped in the HVR1 sequence space, which was visualized as a network of 11,319 sequences. The HVR1 variants with a greater network centrality showed a broader cross-immunoreactivity. The entire sequence space is explored by each HCV genotype and subtype. These findings indicate that HVR1 antigenic diversity is extensively convergent and effectively limited, suggesting significant implications for vaccine development. |
Neurovascular complications of iatrogenic fusarium solani meningitis
Strong N , Meeks G , Sheth SA , McCullough L , Villalba JA , Tan C , Barreto A , Wanger A , McDonald M , Kan P , Shaltoni H , Campo Maldonado J , Parada V , Hassan AE , Reagan-Steiner S , Chiller T , Gold JAW , Smith DJ , Ostrosky-Zeichner L . N Engl J Med 2024 390 (6) 522-529 A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days. |
Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray (preprint)
Camerini D , Randall AZ , Trappl-Kimmons K , Oberai A , Hung C , Edgar J , Shandling A , Huynh V , Teng AA , Hermanson G , Pablo JV , Stumpf MM , Lester SN , Harcourt J , Tamin A , Rasheed M , Thornburg NJ , Satheshkumar PS , Liang X , Kennedy RB , Yee A , Townsend M , Campo JJ . medRxiv 2021 2021.01.14.21249690 The emergence and rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of varying lengths and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multi-coronavirus arrays to identify specific antibody reactivity. High level IgG, IgM and IgA reactivity to structural proteins S, M and N, as well as accessory proteins, of SARS-CoV-2 were observed that was specific to COVID-19 patients. Overlapping 100, 50 and 30 amino acid fragments of SARS-CoV-2 proteins identified antigenic regions. Numerous proteins of SARS-CoV, MERS-CoV and the endemic human coronaviruses, HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients.Competing Interest StatementDavid Camerini, Arlo Z. Randall, Amit Oberai, Christopher Hung, Joshua Edgar, Adam Shandling, Vu Huynh, Andy A. Teng, Gary Hermanson, Jozelyn V. Pablo, Xiaowu Liang, Angela Yee and Joseph J. Campo are employees of Antigen Discovery Inc. In addition, Xiaowu Liang and Angela Yee have an equity interest in Antigen Discovery Inc. The other authors declare non competing interests.Funding StatementNo external funding was used in this study.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study was approved by the Mayo Clinic Human Subjects Institutional Review Board and the Centers for Disease Control and Prevention Human Subjects Office.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data are freely available. |
Primary case inference in viral outbreaks through analysis of intra-host variant population (preprint)
Gussler JW , Campo DS , Dimitrova Z , Skums P , Khudyakov Y . bioRxiv 2020 2020.09.18.303131 Investigation of outbreaks to identify the primary case is crucial for the interruption and prevention of transmission of infectious diseases. These individuals may have a higher risk of participating in near future transmission events when compared to the other patients in the outbreak, so directing more transmission prevention resources towards these individuals is a priority. Genetic characterization of intra-host viral populations, although highly efficient in the identification of transmission clusters, is not as efficient in routing transmissions during outbreaks, owing to complexity of viral evolution. Here, we present a new computational framework, PYCIVO: primary case inference in viral outbreaks. This framework expands upon our earlier work in development of QUENTIN, which builds a probabilistic disease transmission tree based on simulation of evolution of intra-host hepatitis C virus (HCV) variants between cases involved in direct transmission during an outbreak. PYCIVO improves upon QUENTIN by also implementing a custom heterogeneity index which empowers PYCIVO to make the important ‘No primary case’ prediction. One or more samples, possibly including the primary case, may have not been sampled, and this designation is meant to account for these scenarios. These approaches were validated using a set of 105 sequence samples from 11 distinct HCV transmission clusters identified during outbreak investigations, in which the primary case was epidemiologically verified. Both models can detect the correct primary case in 9 out of 11 transmission clusters (81.8%). However, while QUENTIN issues erroneous predictions on the remaining 2 transmission clusters, PYCIVO issues a null output for these clusters, giving it an effective prediction accuracy of 100%. To further evaluate accuracy of the inference, we created 10 modified transmission clusters in which the primary case had been removed. In this scenario, PYCIVO was able to correctly identify that there was no primary case in 8/10 (80%) of these modified clusters. This model was validated with HCV; however, this approach may be applicable to other microbial pathogens.A version of this software is publicly available at the following url: https://www.github.com/walkergussler/PYCIVO |
Fast estimation of genetic relatedness between members of heterogeneous populations of closely related genomic variants (preprint)
Tsyvina V , Campo DS , Sims S , Zelikovsky A , Khudyakov Y , Skums P . bioRxiv 2018 324418 Many biological analysis tasks require extraction of families of genetically similar sequences from large datasets produced by Next-generation Sequencing (NGS). Such tasks include detection of viral transmissions by analysis of all genetically close pairs of sequences from viral datasets sampled from infected individuals or studying of evolution of viruses or immune repertoires by analysis of network of intra-host viral variants or antibody clonotypes formed by genetically close sequences. The most obvious naĻeve algorithms to extract such sequence families are impractical in light of the massive size of modern NGS datasets. In this paper, we present fast and scalable k-mer-based framework to perform such sequence similarity queries efficiently, which specifically targets data produced by deep sequencing of heterogeneous populations such as viruses. The tool is freely available for download at https://github.com/vyacheslav-tsivina/signature-sj |
Polyvalent immunization elicits a synergistic broadly neutralizing immune response to hypervariable region 1 variants of hepatitis C virus
Mosa AI , Campo DS , Khudyakov Y , AbouHaidar MG , Gehring AJ , Zahoor A , Ball JK , Urbanowicz RA , Feld JJ . Proc Natl Acad Sci U S A 2023 120 (24) e2220294120 A hepatitis C virus (HCV) vaccine is urgently needed. Vaccine development has been hindered by HCV's genetic diversity, particularly within the immunodominant hypervariable region 1 (HVR1). Here, we developed a strategy to elicit broadly neutralizing antibodies to HVR1, which had previously been considered infeasible. We first applied a unique information theory-based measure of genetic distance to evaluate phenotypic relatedness between HVR1 variants. These distances were used to model the structure of HVR1's sequence space, which was found to have five major clusters. Variants from each cluster were used to immunize mice individually, and as a pentavalent mixture. Sera obtained following immunization neutralized every variant in a diverse HCVpp panel (n = 10), including those resistant to monovalent immunization, and at higher mean titers (1/ID(50) = 435) than a glycoprotein E2 (1/ID(50) = 205) vaccine. This synergistic immune response offers a unique approach to overcoming antigenic variability and may be applicable to other highly mutable viruses. |
A Novel Information-Theory-Based Genetic Distance That Approximates Phenotypic Differences.
Campo DS , Mosa A , Khudyakov Y . J Comput Biol 2023 30 (4) 420-431 Application of genetic distances to measure phenotypic relatedness is a challenging task, reflecting the complex relationship between genotype and phenotype. Accurate assessment of proximity among sequences with different phenotypic traits depends on how strongly the chosen distance is associated with structural and functional properties. In this study, we present a new distance measure Mutual Information and Entropy H (MIH) for categorical data such as nucleotide or amino acid sequences. MIH applies an information matrix (IM), which is calculated from the data and captures heterogeneity of individual positions as measured by Shannon entropy and coordinated substitutions among positions as measured by mutual information. In general, MIH assigns low weights to differences occurring at high entropy positions or at dependent positions. MIH distance was compared with other common distances on two experimental and two simulated data sets. MIH showed the best ability to distinguish cross-immunoreactive sequence pairs from non-cross-immunoreactive pairs of variants of the hepatitis C virus hypervariable region 1 (26,883 pairwise comparisons), and Major Histocompatibility Complex (MHC) binding peptides (n = 181) from non-binding peptides (n = 129). Analysis of 74 simulated RNA secondary structures also showed that the ratio between MIH distance of sequences from the same RNA structure and MIH of sequences from different structures is three orders of magnitude greater than for Hamming distances. These findings indicate that lower MIH between two sequences is associated with greater probability of the sequences to belong to the same phenotype. Examination of rule-based phenotypes generated in silico showed that (1) MIH is strongly associated with phenotypic differences, (2) IM of sequences under selection is very different from IM generated under random scenarios, and (3) IM is robust to sampling. In conclusion, MIH strongly approximates structural/functional distances and should have important applications to a wide range of biological problems, including evolution, artificial selection of biological functions and structures, and measuring phenotypic similarity. |
Retrospective molecular investigation of Mayaro and Oropouche viruses at the human-animal interface in West-central Brazil, 2016-2018.
Dias HG , de Lima RC , Barbosa LS , Souza TMA , Badolato-Correa J , Maia LMS , Ferreira RDS , Neves Nads , Costa MCS , Martins LR , Souza EM , Carvalho MDS , Araujo-Oliveira A , Marques WA , Sabino-Santos G , Marques MS , Macedo GC , Nantes WAG , Santos FM , Netto CC , Morgado TO , Bianchini MA , Correa SHR , Almeida JR , Campos LP , Souza IM , Barreto WTG , Porfírio G , Alencar JAF , Herrera HM , Shlessarenko RD , Cunha RVD , Azeredo EL , Salyer SJ , Komar N , Pauvolid-Corrêa A , Dos Santos FB . PLoS One 2022 17 (11) e0277612 Mayaro virus (MAYV, Togaviridae) and Oropouche orthobunyavirus (OROV, Peribunyaviridae) are emerging enzootic arboviruses in Latin America. Outbreaks of febrile illness associated with MAYV and OROV have been reported among humans mainly in the northern region of Brazil since the 1980s, and recent data suggest these viruses have circulated also in more populated areas of western Brazil. MAYV shares mosquito vectors with yellow fever virus and it has been historically detected during yellow fever epidemics. Aiming to investigate the transmission of OROV and MAYV at the human-animal interface during a yellow fever, chikungunya and Zika outbreaks in Brazil, we conducted a retrospective molecular investigation in 810 wild and domestic animals, 106 febrile patients, and 22.931 vectors collected from 2016 to 2018 in Cuiaba and Campo Grande metropolitan regions, western Brazil. All samples tested negative for OROV and MAYV RNA by RT-qPCR. Findings presented here suggest no active circulation of MAYV and OROV in the sampled hosts. Active surveillance and retrospective investigations are instrumental approaches for the detection of cryptic and subclinical activity of enzootic arboviruses and together serve as a warning system to implement appropriate actions to prevent outbreaks. |
Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria.
Talundzic E , Scott S , Owino SO , Campo DS , Lucchi NW , Udhayakumar V , Moore JM , Peterson DS . Pathogens 2022 11 (5) The Plasmodium falciparum protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the var2csa DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique var2csa sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some var2csa sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. |
Dynamics of Triatoma infestans populations in the Paraguayan Chaco: Population genetic analysis of household reinfestation following vector control.
RojasdeArias A , Messenger LA , Rolon M , Vega MC , Acosta N , Villalba C , Marcet PL . PLoS One 2022 17 (2) e0263465 BACKGROUND: Although domestic infestations by Triatoma infestans have been successfully controlled across Latin America, in areas of the Gran Chaco region, recurrent post-spraying house colonization continues to be a significant challenge, jeopardizing Chagas disease vector control and maintaining active Trypanosoma cruzi transmission. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the dynamics of triatomine reinfestation in a rural area of the Paraguayan Chaco, genetic characterization (based on 10 microsatellite loci and cytochrome B sequence polymorphisms) was performed on baseline and reinfestant T. infestans (n = 138) from four indigenous communities and adjacent sylvatic sites. House quality and basic economic activities were assessed across the four communities. Significant genetic differentiation was detected among all baseline triatomine populations. Faster reinfestation was observed in the communities with higher infestation rates pre-spraying. Baseline and reinfestant populations from the same communities were not genetically different, but two potentially distinct processes of reinfestation were evident. In Campo Largo, the reinfestant population was likely founded by domestic survivor foci, with reduced genetic diversity relative to the baseline population. However, in 12 de Junio, reinfestant bugs were likely derived from different sources, including survivors from the pre-spraying population and sympatric sylvatic bugs, indicative of gene-flow between these habitats, likely driven by high human mobility and economic activities in adjacent sylvatic areas. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that sylvatic T. infestans threatens vector control strategies, either as a reinfestation source or by providing a temporary refuge during insecticide spraying. Passive anthropogenic importation of T. infestans and active human interactions with neighboring forested areas also played a role in recolonization. Optimization of spraying, integrated community development and close monitoring of sylvatic areas should be considered when implementing vector control activities in the Gran Chaco. |
Primary case inference in viral outbreaks through analysis of intra-host variant population.
Gussler JW , Campo DS , Dimitrova Z , Skums P , Khudyakov Y . BMC Bioinformatics 2022 23 (1) 62 BACKGROUND: Investigation of outbreaks to identify the primary case is crucial for the interruption and prevention of transmission of infectious diseases. These individuals may have a higher risk of participating in near future transmission events when compared to the other patients in the outbreak, so directing more transmission prevention resources towards these individuals is a priority. Although the genetic characterization of intra-host viral populations can aid the identification of transmission clusters, it is not trivial to determine the directionality of transmissions during outbreaks, owing to complexity of viral evolution. Here, we present a new computational framework, PYCIVO: primary case inference in viral outbreaks. This framework expands upon our earlier work in development of QUENTIN, which builds a probabilistic disease transmission tree based on simulation of evolution of intra-host hepatitis C virus (HCV) variants between cases involved in direct transmission during an outbreak. PYCIVO improves upon QUENTIN by also adding a custom heterogeneity index and identifying the scenario when the primary case may have not been sampled. RESULTS: These approaches were validated using a set of 105 sequence samples from 11 distinct HCV transmission clusters identified during outbreak investigations, in which the primary case was epidemiologically verified. Both models can detect the correct primary case in 9 out of 11 transmission clusters (81.8%). However, while QUENTIN issues erroneous predictions on the remaining 2 transmission clusters, PYCIVO issues a null output for these clusters, giving it an effective prediction accuracy of 100%. To further evaluate accuracy of the inference, we created 10 modified transmission clusters in which the primary case had been removed. In this scenario, PYCIVO was able to correctly identify that there was no primary case in 8/10 (80%) of these modified clusters. This model was validated with HCV; however, this approach may be applicable to other microbial pathogens. CONCLUSIONS: PYCIVO improves upon QUENTIN by also implementing a custom heterogeneity index which empowers PYCIVO to make the important 'No primary case' prediction. One or more samples, possibly including the primary case, may have not been sampled, and this designation is meant to account for these scenarios. |
Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray.
Camerini D , Randall AZ , Trappl-Kimmons K , Oberai A , Hung C , Edgar J , Shandling A , Huynh V , Teng AA , Hermanson G , Pablo JV , Stumpf MM , Lester SN , Harcourt J , Tamin A , Rasheed M , Thornburg NJ , Satheshkumar PS , Liang X , Kennedy RB , Yee A , Townsend M , Campo JJ . Microbiol Spectr 2021 9 (2) e0141621 The rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the COVID-19 pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of various lengths, and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multicoronavirus arrays to identify specific antibody reactivity. High-level IgG, IgM, and IgA reactivity to structural proteins S, M, and N of SARS-CoV-2, as well as accessory proteins such as ORF3a and ORF7a, were observed that were specific to COVID-19 patients. Antibody reactivity against overlapping 100-, 50-, and 30-amino acid fragments of SARS-CoV-2 proteins was used to identify antigenic regions. Numerous proteins of SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and the endemic human coronaviruses HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM, and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. Whereas unexposed individuals had minimal reactivity against SARS-CoV-2 proteins that poorly correlated with reactivity against HCoV-NL63 and HCoV-OC43 S2 and N proteins, COVID-19 patient sera had higher correlation between SARS-CoV-2 and HCoV responses, suggesting that de novo antibodies against SARS-CoV-2 cross-react with HCoV epitopes. Array responses were compared with validated spike protein-specific IgG enzyme-linked immunosorbent assays (ELISAs), showing agreement between orthologous methods. SARS-CoV-2 microneutralization titers were low in the COVID-19 patient sera but correlated with array responses against S and N proteins. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients. IMPORTANCE With novel mutant SARS-CoV-2 variants of concern on the rise, knowledge of immune specificities against SARS-CoV-2 proteins is increasingly important for understanding the impact of structural changes in antibody-reactive protein epitopes on naturally acquired and vaccine-induced immunity, as well as broader topics of cross-reactivity and viral evolution. A multi-coronavirus protein microarray used to map the binding of COVID-19 patient antibodies to SARS-CoV-2 proteins and protein fragments as well as to the proteins of four other coronaviruses that infect humans has shown specific regions of SARS-CoV-2 proteins that are highly reactive with patient antibodies and revealed cross-reactivity of these antibodies with other human coronaviruses. These data and the multi-coronavirus protein microarray tool will help guide further studies of the antibody response to COVID-19 and to vaccination against this worldwide pandemic. |
Convex hulls in hamming space enable efficient search for similarity and clustering of genomic sequences.
Campo DS , Khudyakov Y . BMC Bioinformatics 2020 21 482 BACKGROUND: In molecular epidemiology, comparison of intra-host viral variants among infected persons is frequently used for tracing transmissions in human population and detecting viral infection outbreaks. Application of Ultra-Deep Sequencing (UDS) immensely increases the sensitivity of transmission detection but brings considerable computational challenges when comparing all pairs of sequences. We developed a new population comparison method based on convex hulls in hamming space. We applied this method to a large set of UDS samples obtained from unrelated cases infected with hepatitis C virus (HCV) and compared its performance with three previously published methods. RESULTS: The convex hull in hamming space is a data structure that provides information on: (1) average hamming distance within the set, (2) average hamming distance between two sets; (3) closeness centrality of each sequence; and (4) lower and upper bound of all the pairwise distances among the members of two sets. This filtering strategy rapidly and correctly removes 96.2% of all pairwise HCV sample comparisons, outperforming all previous methods. The convex hull distance (CHD) algorithm showed variable performance depending on sequence heterogeneity of the studied populations in real and simulated datasets, suggesting the possibility of using clustering methods to improve the performance. To address this issue, we developed a new clustering algorithm, k-hulls, that reduces heterogeneity of the convex hull. This efficient algorithm is an extension of the k-means algorithm and can be used with any type of categorical data. It is 6.8-times more accurate than k-mode, a previously developed clustering algorithm for categorical data. CONCLUSIONS: CHD is a fast and efficient filtering strategy for massively reducing the computational burden of pairwise comparison among large samples of sequences, and thus, aiding the calculation of transmission links among infected individuals using threshold-based methods. In addition, the convex hull efficiently obtains important summary metrics for intra-host viral populations. |
Accurate spatiotemporal mapping of drug overdose deaths by machine learning of drug-related web-searches.
Campo DS , Gussler JW , Sue A , Skums P , Khudyakov Y . PLoS One 2020 15 (12) e0243622 Persons who inject drugs (PWID) are at increased risk for overdose death (ODD), infections with HIV, hepatitis B (HBV) and hepatitis C virus (HCV), and noninfectious health conditions. Spatiotemporal identification of PWID communities is essential for developing efficient and cost-effective public health interventions for reducing morbidity and mortality associated with injection-drug use (IDU). Reported ODDs are a strong indicator of the extent of IDU in different geographic regions. However, ODD quantification can take time, with delays in ODD reporting occurring due to a range of factors including death investigation and drug testing. This delayed ODD reporting may affect efficient early interventions for infectious diseases. We present a novel model, Dynamic Overdose Vulnerability Estimator (DOVE), for assessment and spatiotemporal mapping of ODDs in different U.S. jurisdictions. Using Google® Web-search volumes (i.e., the fraction of all searches that include certain words), we identified a strong association between the reported ODD rates and drug-related search terms for 2004-2017. A machine learning model (Extremely Random Forest) was developed to produce yearly ODD estimates at state and county levels, as well as monthly estimates at state level. Regarding the total number of ODDs per year, DOVE's error was only 3.52% (Median Absolute Error, MAE) in the United States for 2005-2017. DOVE estimated 66,463 ODDs out of the reported 70,237 (94.48%) during 2017. For that year, the MAE of the individual ODD rates was 4.43%, 7.34%, and 12.75% among yearly estimates for states, yearly estimates for counties, and monthly estimates for states, respectively. These results indicate suitability of the DOVE ODD estimates for dynamic IDU assessment in most states, which may alert for possible increased morbidity and mortality associated with IDU. ODD estimates produced by DOVE offer an opportunity for a spatiotemporal ODD mapping. Timely identification of potential mortality trends among PWID might assist in developing efficient ODD prevention and HBV, HCV, and HIV infection elimination programs by targeting public health interventions to the most vulnerable PWID communities. |
High prevalence of Hepatitis C Virus infection among people who use crack cocaine in an important international drug trafficking route in Central-West Region Brazil.
Castro VOL , Kamili S , Forbi JC , Stabile AC , da Silva EF , do Valle Leone de Oliveira SM , de Carvalho PRT , Puga MAM , Tanaka TSO , do Lago BV , Ibanhes ML , Araujo A , Tejada-Strop A , Lin Y , Xia GL , Sue A , Teles SA , Motta-Castro ARC . Infect Genet Evol 2020 85 104488 In this study, the prevalence rate, associated risk factors and genetic diversity of hepatitis C virus (HCV) infection were determined among people who use crack from an international drug trafficking route in Central-West, Brazil. Blood samples were collected from 700 users of crack from Campo Grande and two border cities of Mato Grosso do Sul State and tested for HCV infection using serological and molecular testing methodologies. Anti-HCV was detected in 31/700 (4.5%, 95% CI: 2.9-6.0%) and HCV RNA in 26/31 (83.9%) of anti-HCV positive samples. Phylogenetic analysis of three HCV sub-genomic regions (5'UTR, NS5B and HVR-1) revealed the circulation of 1a (73.9%), 1b (8.7%) and 3a (17.4%) genotypes. Next-generation sequencing and phylogenetic analysis of intra-host viral populations of HCV HVR-1 showed a significant variation in intra-host genetic diversity among infected individuals, with 58.8% composed of more than one sub-population. Bayesian analysis estimated that the most recent common HCV ancestor for strains identified here was introduced to this region after 1975 following expansion of intravenous drug use in Brazil. Multivariate analyses showed that only 'ever having injected drugs' was independently associated with HCV infection. These results indicate an increasing spread of multiple HCV strains requiring public health intervention, such as harm reduction, testing services and treatment among crack users in this important border region of Central Brazil. |
Machine learning can accelerate discovery and application of cyber-molecular cancer diagnostics.
Campo DS , Khudyakov Y . J Med Artif Intell 2020 3 (7) Accurate and early cancer diagnosis is fundamental for clinical management and public health. Unfortunately, the biological complexity of cancer confounds the development of effective diagnostic approaches to its detection. Histological examination of tissue samples obtained by biopsy directly from solid tumors and imaging technologies remain as the mainstays of cancer diagnostics. The liquid biopsy concept aims to overcome the shortcomings of these onco-diagnostics by detecting tumor-derived biomarkers such as circulating tumor cells, extracellular vesicles, nucleosomes, proteins, antigens, and extracellular nucleic acids in blood (1). |
Education and training to build capacity in Total Worker Health(R): Proposed competencies for an emerging field
Newman LS , Scott JG , Childress A , Linnan L , Newhall WJ , McLellan DL , Campo S , Freewynn S , Hammer LB , Leff M , Macy G , Maples EH , Rogers B , Rohlman DS , Tenney L , Watkins C . J Occup Environ Med 2020 62 (8) e384-e391 OBJECTIVE: Establishment of core competencies for education and training of professionals entering the emerging field of Total Worker Health(R). METHODS: Compilation and distillation of information obtained over a five-year period from Total Worker Health symposia, workshops, and academic offerings, plus contributions from key stakeholders regarding education and training needs. RESULTS: A proposed set of Total Worker Health competencies aligns under six broad domains: Subject Matter Expertise; Advocacy and Engagement; Program Planning, Implementation and Evaluation; Communications and Dissemination; Leadership and Management; and Partnership Building and Coordination. CONCLUSIONS: Proposed set of core competencies will help standardize education and training for professionals being trained in Total Worker Health. It serves as an invitation for further input from stakeholders in academia, business, labor, and government. |
Entropy of mitochondrial DNA circulating in blood is associated with hepatocellular carcinoma.
Campo DS , Nayak V , Srinivasamoorthy G , Khudyakov Y . BMC Med Genomics 2019 12 74 BACKGROUND: Ultra-Deep Sequencing (UDS) enabled identification of specific changes in human genome occurring in malignant tumors, with current approaches calling for the detection of specific mutations associated with certain cancers. However, such associations are frequently idiosyncratic and cannot be generalized for diagnostics. Mitochondrial DNA (mtDNA) has been shown to be functionally associated with several cancer types. Here, we study the association of intra-host mtDNA diversity with Hepatocellular Carcinoma (HCC). RESULTS: UDS mtDNA exome data from blood of patients with HCC (n = 293) and non-cancer controls (NC, n = 391) were used to: (i) measure the genetic heterogeneity of nucleotide sites from the entire population of intra-host mtDNA variants rather than to detect specific mutations, and (ii) apply machine learning algorithms to develop a classifier for HCC detection. Average total entropy of HCC mtDNA is 1.24-times lower than of NC mtDNA (p = 2.84E-47). Among all polymorphic sites, 2.09% had a significantly different mean entropy between HCC and NC, with 0.32% of the HCC mtDNA sites having greater (p < 0.05) and 1.77% of the sites having lower mean entropy (p < 0.05) as compared to NC. The entropy profile of each sample was used to further explore the association between mtDNA heterogeneity and HCC by means of a Random Forest (RF) classifier The RF-classifier separated 232 HCC and 232 NC patients with accuracy of up to 99.78% and average accuracy of 92.23% in the 10-fold cross-validation. The classifier accurately separated 93.08% of HCC (n = 61) and NC (n = 159) patients in a validation dataset that was not used for the RF parameter optimization. CONCLUSIONS: Polymorphic sites contributing most to the mtDNA association with HCC are scattered along the mitochondrial genome, affecting all mitochondrial genes. The findings suggest that application of heterogeneity profiles of intra-host mtDNA variants from blood may help overcome barriers associated with the complex association of specific mutations with cancer, enabling the development of accurate, rapid, inexpensive and minimally invasive diagnostic detection of cancer. |
Research methodologies for Total Worker Health(R): Proceedings from a workshop
Tamers SL , Goetzel R , Kelly KM , Luckhaupt S , Nigam J , Pronk NP , Rohlman DS , Baron S , Brosseau LM , Bushnell T , Campo S , Chang CC , Childress A , Chosewood LC , Cunningham T , Goldenhar LM , Huang TT , Hudson H , Linnan L , Newman LS , Olson R , Ozminkowski RJ , Punnett L , Schill A , Scholl J , Sorensen G . J Occup Environ Med 2018 60 (11) 968-978 OBJECTIVE: There is growing interest in the NIOSH Total Worker Health program, specifically in the process of designing and implementing safer, health-promoting work and workplaces. A Total Worker Health (TWH) Research Methodology Workshop was convened to discuss research methods and future needs. METHODS: Twenty-six experts in occupational safety and health and related fields reviewed and discussed current methodological and measurement issues and those showing promise. RESULTS: TWH intervention studies face the same challenges as other workplace intervention studies and some unique ones. Examples are provided of different approaches and their applications to TWH intervention studies, and desired developments in the TWH literature. CONCLUSIONS: This report discusses and outlines principles important to building the TWH intervention research base. Rigorous, valid methodologic, and measurement approaches are needed for TWH intervention as well as for basic/etiologic, translational, and surveillance research. |
Association of male circumcision with women's knowledge of its biomedical effects and with their sexual satisfaction and function: A systematic review
Grund JM , Bryant TS , Toledo C , Jackson I , Curran K , Zhou S , Del Campo JM , Yang L , Kivumbi A , Li P , Bock N , Taliano J , Davis SM . AIDS Behav 2018 23 (5) 1104-1114 Male circumcision (MC) is a key HIV prevention intervention for men in countries with high HIV prevalence. Women's understanding of MC is important but poorly understood. We conducted a systematic review including women's knowledge of MC's biomedical impacts and its association with female sexual satisfaction and function through October 2017. Thirty-eight articles were identified: thirty-two with knowledge outcomes, seven with sexual satisfaction, and four with sexual function (N = 38). Respondent proportions aware MC protects men from HIV were 9.84-91.8% (median 60.0%). Proportions aware MC protects men from STIs were 14.3-100% (72.6%). Proportions aware MC partially protects men from HIV were 37.5-82% (50.7%). Proportions aware MC is not proven to protect women from infection by an HIV-positive partner were 90.0-96.8% (93.0%). No increases over time were noted. Women's MC knowledge is variable. Education could help women support MC and make better-informed sexual decisions. |
Fast estimation of genetic relatedness between members of heterogeneous populations of closely related genomic variants.
Tsyvina V , Campo DS , Sims S , Zelikovsky A , Khudyakov Y , Skums P . BMC Bioinformatics 2018 19 360 BACKGROUND: Many biological analysis tasks require extraction of families of genetically similar sequences from large datasets produced by Next-generation Sequencing (NGS). Such tasks include detection of viral transmissions by analysis of all genetically close pairs of sequences from viral datasets sampled from infected individuals or studying of evolution of viruses or immune repertoires by analysis of network of intra-host viral variants or antibody clonotypes formed by genetically close sequences. The most obvious naieve algorithms to extract such sequence families are impractical in light of the massive size of modern NGS datasets. RESULTS: In this paper, we present fast and scalable k-mer-based framework to perform such sequence similarity queries efficiently, which specifically targets data produced by deep sequencing of heterogeneous populations such as viruses. It shows better filtering quality and time performance when comparing to other tools. The tool is freely available for download at https://github.com/vyacheslav-tsivina/signature-sj CONCLUSION: The proposed tool allows for efficient detection of genetic relatedness between genomic samples produced by deep sequencing of heterogeneous populations. It should be especially useful for analysis of relatedness of genomes of viruses with unevenly distributed variable genomic regions, such as HIV and HCV. For the future we envision, that besides applications in molecular epidemiology the tool can also be adapted to immunosequencing and metagenomics data. |
Automated quality control for a molecular surveillance system.
Sims S , Longmire AG , Campo DS , Ramachandran S , Medrzycki M , Ganova-Raeva L , Lin Y , Sue A , Thai H , Zelikovsky A , Khudyakov Y . BMC Bioinformatics 2018 19 358 BACKGROUND: Molecular surveillance and outbreak investigation are important for elimination of hepatitis C virus (HCV) infection in the United States. A web-based system, Global Hepatitis Outbreak and Surveillance Technology (GHOST), has been developed using Illumina MiSeq-based amplicon sequence data derived from the HCV E1/E2-junction genomic region to enable public health institutions to conduct cost-effective and accurate molecular surveillance, outbreak detection and strain characterization. However, as there are many factors that could impact input data quality to which the GHOST system is not completely immune, accuracy of epidemiological inferences generated by GHOST may be affected. Here, we analyze the data submitted to the GHOST system during its pilot phase to assess the nature of the data and to identify common quality concerns that can be detected and corrected automatically. RESULTS: The GHOST quality control filters were individually examined, and quality failure rates were measured for all samples, including negative controls. New filters were developed and introduced to detect primer dimers, loss of specimen-specific product, or short products. The genotyping tool was adjusted to improve the accuracy of subtype calls. The identification of "chordless" cycles in a transmission network from data generated with known laboratory-based quality concerns allowed for further improvement of transmission detection by GHOST in surveillance settings. Parameters derived to detect actionable common quality control anomalies were incorporated into the automatic quality control module that rejects data depending on the magnitude of a quality problem, and warns and guides users in performing correctional actions. The guiding responses generated by the system are tailored to the GHOST laboratory protocol. CONCLUSIONS: Several new quality control problems were identified in MiSeq data submitted to GHOST and used to improve protection of the system from erroneous data and users from erroneous inferences. The GHOST system was upgraded to include identification of causes of erroneous data and recommendation of corrective actions to laboratory users. |
Intelligent Network DisRuption Analysis (INDRA): A targeted strategy for efficient interruption of hepatitis C transmissions
Campo DS , Khudyakov Y . Infect Genet Evol 2018 63 204-215 Hepatitis C virus (HCV) infection is a global public health problem. The implementation of public health interventions (PHI) to control HCV infection could effectively interrupt HCV transmission. PHI targeting high-risk populations, e.g., people who inject drugs (PWID), are the most efficient but there is a lack of tools for prioritizing individuals within a high-risk community. Here, we present Intelligent Network DisRuption Analysis (INDRA), a targeted strategy for efficient interruption of hepatitis C transmissions.Using a large HCV transmission network among PWID in Indiana as an example, we compare effectiveness of random and targeted strategies in reducing the rate of HCV transmission in two settings: (1) long-established and (2) rapidly spreading infections (outbreak). Identification of high centrality for the network nodes co-infected with HIV or>1 HCV subtype indicates that the network structure properly represents the underlying contacts among PWID relevant to the transmission of these infections. Changes in the network's global efficiency (GE) were used as a measure of the PHI effects. In setting 1, simulation experiments showed that a 50% GE reduction can be achieved by removing 11.2 times less nodes using targeted vs random strategies. A greater effect of targeted strategies on GE was consistently observed when networks were simulated: (1) with a varying degree of errors in node sampling and link assignment, and (2) at different levels of transmission reduction at affected nodes. In simulations considering a 10% removal of infected nodes, targeted strategies were ~2.8 times more effective than random in reducing incidence. Peer-education intervention (PEI) was modeled as a probabilistic distribution of actionable knowledge of safe injection practices from the affected node to adjacent nodes in the network. Addition of PEI to the models resulted in a 2-3 times greater reduction in incidence than from direct PHI alone. In setting 2, however, random direct PHI were ~3.2 times more effective in reducing incidence at the simulated conditions. Nevertheless, addition of PEI resulted in a ~1.7-fold greater efficiency of targeted PHI. In conclusion, targeted PHI facilitated by INDRA outperforms random strategies in decreasing circulation of long-established infections. Network-based PEI may amplify effects of PHI on incidence reduction in both settings. |
Use of the kurtosis statistic in an evaluation of the effects of noise and solvent exposures on the hearing thresholds of workers: An exploratory study
Fuente A , Qiu W , Zhang M , Xie H , Kardous CA , Campo P , Morata TC . J Acoust Soc Am 2018 143 (3) 1704 The aim of this exploratory study was to examine whether the kurtosis metric can contribute to investigations of the effects of combined exposure to noise and solvents on human hearing thresholds. Twenty factory workers exposed to noise and solvents along with 20 workers of similar age exposed only to noise in eastern China were investigated using pure-tone audiometry (1000-8000 Hz). Exposure histories and shift-long noise recording files were obtained for each participant. The data were used in the calculation of the cumulative noise exposure (CNE) and CNE adjusted by the kurtosis metric for each participant. Passive samplers were used to measure solvent concentrations for each worker exposed to solvents over the full work shift. Results showed an interaction between noise exposure and solvents for the hearing threshold at 6000 Hz. This effect was observed only when the CNE level was adjusted by the kurtosis metric. |
QUENTIN: reconstruction of disease transmissions from viral quasispecies genomic data.
Skums P , Zelikovsky A , Singh R , Gussler W , Dimitrova Z , Knyazev S , Mandric I , Ramachandran S , Campo D , Jha D , Bunimovich L , Costenbader E , Sexton C , O'Connor S , Xia GL , Khudyakov Y . Bioinformatics 2018 34 (1) 163-170 Motivation: Genomic analysis has become one of the major tools for disease outbreak investigations. However, existing computational frameworks for inference of transmission history from viral genomic data often do not consider intra-host diversity of pathogens and heavily rely on additional epidemiological data, such as sampling times and exposure intervals. This impedes genomic analysis of outbreaks of highly mutable viruses associated with chronic infections, such as human immunodeficiency virus and hepatitis C virus, whose transmissions are often carried out through minor intra-host variants, while the additional epidemiological information often is either unavailable or has a limited use. Results: The proposed framework QUasispecies Evolution, Network-based Transmission INference (QUENTIN) addresses the above challenges by evolutionary analysis of intra-host viral populations sampled by deep sequencing and Bayesian inference using general properties of social networks relevant to infection dissemination. This method allows inference of transmission direction even without the supporting case-specific epidemiological information, identify transmission clusters and reconstruct transmission history. QUENTIN was validated on experimental and simulated data, and applied to investigate HCV transmission within a community of hosts with high-risk behavior. It is available at https://github.com/skumsp/QUENTIN. Contact: pskums@gsu.edu or alexz@cs.gsu.edu or rahul@sfsu.edu or yek0@cdc.gov. Supplementary information: Supplementary data are available at Bioinformatics online. |
Transmissibility of intra-host hepatitis C virus variants.
Campo DS , Zhang J , Ramachandran S , Khudyakov Y . BMC Genomics 2017 18 881 BACKGROUND: Intra-host hepatitis C virus (HCV) populations are genetically heterogeneous and organized in subpopulations. With the exception of blood transfusions, transmission of HCV occurs via a small number of genetic variants, the effect of which is frequently described as a bottleneck. Stochasticity of transmission associated with the bottleneck is usually used to explain genetic differences among HCV populations identified in the source and recipient cases, which may be further exacerbated by intra-host HCV evolution and differential biological capacity of HCV variants to successfully establish a population in a new host. RESULTS: Transmissibility was formulated as a property that can be measured from experimental Ultra-Deep Sequencing (UDS) data. The UDS data were obtained from one large hepatitis C outbreak involving an epidemiologically defined source and 18 recipient cases. k-Step networks of HCV variants were constructed and used to identify a potential association between transmissibility and network centrality of individual HCV variants from the source. An additional dataset obtained from nine other HCV outbreaks with known directionality of transmission was used for validation. Transmissibility was not found to be dependent on high frequency of variants in the source, supporting the earlier observations of transmission of minority variants. Among all tested measures of centrality, the highest correlation of transmissibility was found with Hamming centrality (r = 0.720; p = 1.57 E-71). Correlation between genetic distances and differences in transmissibility among HCV variants from the source was found to be 0.3276 (Mantel Test, p = 9.99 E-5), indicating association between genetic proximity and transmissibility. A strong correlation ranging from 0.565-0.947 was observed between Hamming centrality and transmissibility in 7 of the 9 additional transmission clusters (p < 0.05). CONCLUSIONS: Transmission is not an exclusively stochastic process. Transmissibility, as formally measured in this study, is associated with certain biological properties that also define location of variants in the genetic space occupied by the HCV strain from the source. The measure may also be applicable to other highly heterogeneous viruses. Besides improving accuracy of outbreak investigations, this finding helps with the understanding of molecular mechanisms contributing to establishment of chronic HCV infection. |
GHOST: global hepatitis outbreak and surveillance technology.
Longmire AG , Sims S , Rytsareva I , Campo DS , Skums P , Dimitrova Z , Ramachandran S , Medrzycki M , Thai H , Ganova-Raeva L , Lin Y , Punkova LT , Sue A , Mirabito M , Wang S , Tracy R , Bolet V , Sukalac T , Lynberg C , Khudyakov Y . BMC Genomics 2017 18 916 BACKGROUND: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Effective HCV outbreak investigation requires comprehensive surveillance and robust case investigation. We previously developed and validated a methodology for the rapid and cost-effective identification of HCV transmission clusters. Global Hepatitis Outbreak and Surveillance Technology (GHOST) is a cloud-based system enabling users, regardless of computational expertise, to analyze and visualize transmission clusters in an independent, accurate and reproducible way. RESULTS: We present and explore performance of several GHOST implemented algorithms using next-generation sequencing data experimentally obtained from hypervariable region 1 of genetically related and unrelated HCV strains. GHOST processes data from an entire MiSeq run in approximately 3 h. A panel of seven specimens was used for preparation of six repeats of MiSeq libraries. Testing sequence data from these libraries by GHOST showed a consistent transmission linkage detection, testifying to high reproducibility of the system. Lack of linkage among genetically unrelated HCV strains and constant detection of genetic linkage between HCV strains from known transmission pairs and from follow-up specimens at different levels of MiSeq-read sampling indicate high specificity and sensitivity of GHOST in accurate detection of HCV transmission. CONCLUSIONS: GHOST enables automatic extraction of timely and relevant public health information suitable for guiding effective intervention measures. It is designed as a virtual diagnostic system intended for use in molecular surveillance and outbreak investigations rather than in research. The system produces accurate and reproducible information on HCV transmission clusters for all users, irrespective of their level of bioinformatics expertise. Improvement in molecular detection capacity will contribute to increasing the rate of transmission detection, thus providing opportunity for rapid, accurate and effective response to outbreaks of hepatitis C. Although GHOST was originally developed for hepatitis C surveillance, its modular structure is readily applicable to other infectious diseases. Worldwide availability of GHOST for the detection of HCV transmissions will foster deeper involvement of public health researchers and practitioners in hepatitis C outbreak investigation. |
Association between male circumcision and women's biomedical health outcomes: a systematic review
Grund JM , Bryant TS , Jackson I , Curran K , Bock N , Toledo C , Taliano J , Zhou S , Del Campo JM , Yang L , Kivumbi A , Li P , Pals S , Davis SM . Lancet Glob Health 2017 5 (11) e1113-e1122 BACKGROUND: Male circumcision reduces men's risk of acquiring HIV and some sexually transmitted infections from heterosexual exposure, and is essential for HIV prevention in sub-Saharan Africa. Studies have also investigated associations between male circumcision and risk of acquisition of HIV and sexually transmitted infections in women. We aimed to review all evidence on associations between male circumcision and women's health outcomes to benefit women's health programmes. METHODS: In this systematic review we searched for peer-reviewed and grey literature publications reporting associations between male circumcision and women's health outcomes up to April 11, 2016. All biomedical (not psychological or social) outcomes in all study types were included. Searches were not restricted by year of publication, or to sub-Saharan Africa. Publications without primary data and not in English were excluded. We extracted data and assessed evidence on each outcome as high, medium, or low consistency on the basis of agreement between publications; outcomes found in fewer than three publications were indeterminate consistency. FINDINGS: 60 publications were included in our assessment. High-consistency evidence was found for five outcomes, with male circumcision protecting against cervical cancer, cervical dysplasia, herpes simplex virus type 2, chlamydia, and syphilis. Medium-consistency evidence was found for male circumcision protecting against human papillomavirus and low-risk human papillomavirus. Although the evidence shows a protective association with HIV, it was categorised as low consistency, because one trial showed an increased risk to female partners of HIV-infected men resuming sex early after male circumcision. Seven outcomes including HIV had low-consistency evidence and six were indeterminate. INTERPRETATION: Scale-up of male circumcision in sub-Saharan Africa has public health implications for several outcomes in women. Evidence that female partners are at decreased risk of several diseases is highly consistent. Synergies between male circumcision and women's health programmes should be explored. FUNDING: US Centers for Disease Control and Prevention and Jhpiego. |
Standardized interpretation of chest radiographs in cases of pediatric pneumonia from the PERCH Study
Fancourt N , Deloria Knoll M , Barger-Kamate B , de Campo J , de Campo M , Diallo M , Ebruke BE , Feikin DR , Gleeson F , Gong W , Hammitt LL , Izadnegahdar R , Kruatrachue A , Madhi SA , Manduku V , Matin FB , Mahomed N , Moore DP , Mwenechanya M , Nahar K , Oluwalana C , Ominde MS , Prosperi C , Sande J , Suntarattiwong P , O'Brien KL . Clin Infect Dis 2017 64 S253-s261 Background.: Chest radiographs (CXRs) are a valuable diagnostic tool in epidemiologic studies of pneumonia. The World Health Organization (WHO) methodology for the interpretation of pediatric CXRs has not been evaluated beyond its intended application as an endpoint measure for bacterial vaccine trials. Methods.: The Pneumonia Etiology Research for Child Health (PERCH) study enrolled children aged 1-59 months hospitalized with WHO-defined severe and very severe pneumonia from 7 low- and middle-income countries. An interpretation process categorized each CXR into 1 of 5 conclusions: consolidation, other infiltrate, both consolidation and other infiltrate, normal, or uninterpretable. Two members of a 14-person reading panel, who had undertaken training and standardization in CXR interpretation, interpreted each CXR. Two members of an arbitration panel provided additional independent reviews of CXRs with discordant interpretations at the primary reading, blinded to previous reports. Further discordance was resolved with consensus discussion. Results.: A total of 4172 CXRs were obtained from 4232 cases. Observed agreement for detecting consolidation (with or without other infiltrate) between primary readers was 78% (kappa = 0.50) and between arbitrators was 84% (kappa = 0.61); agreement for primary readers and arbitrators across 5 conclusion categories was 43.5% (kappa = 0.25) and 48.5% (kappa = 0.32), respectively. Disagreement was most frequent between conclusions of other infiltrate and normal for both the reading panel and the arbitration panel (32% and 30% of discordant CXRs, respectively). Conclusions.: Agreement was similar to that of previous evaluations using the WHO methodology for detecting consolidation, but poor for other infiltrates despite attempts at a rigorous standardization process. |
- Page last reviewed:Feb 1, 2024
- Page last updated:May 06, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure