RESUMO
The dichotomous model of "drivers" and "passengers" in cancer posits that only a few mutations in a tumor strongly affect its progression, with the remaining ones being inconsequential. Here, we leveraged the comprehensive variant dataset from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) project to demonstrate that-in addition to the dichotomy of high- and low-impact variants-there is a third group of medium-impact putative passengers. Moreover, we also found that molecular impact correlates with subclonal architecture (i.e., early versus late mutations), and different signatures encode for mutations with divergent impact. Furthermore, we adapted an additive-effects model from complex-trait studies to show that the aggregated effect of putative passengers, including undetected weak drivers, provides significant additional power (â¼12% additive variance) for predicting cancerous phenotypes, beyond PCAWG-identified driver mutations. Finally, this framework allowed us to estimate the frequency of potential weak-driver mutations in PCAWG samples lacking any well-characterized driver alterations.
Assuntos
Genoma Humano/genética , Genômica/métodos , Mutação/genética , Neoplasias/genética , Análise Mutacional de DNA/métodos , Progressão da Doença , Humanos , Neoplasias/patologia , Sequenciamento Completo do GenomaRESUMO
To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
Assuntos
Comunicação Celular/fisiologia , RNA/metabolismo , Adulto , Líquidos Corporais/química , Ácidos Nucleicos Livres/metabolismo , MicroRNA Circulante/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , SoftwareRESUMO
MOTIVATION: While many quantum computing (QC) methods promise theoretical advantages over classical counterparts, quantum hardware remains limited. Exploiting near-term QC in computer-aided drug design (CADD) thus requires judicious partitioning between classical and quantum calculations. RESULTS: We present HypaCADD, a hybrid classical-quantum workflow for finding ligands binding to proteins, while accounting for genetic mutations. We explicitly identify modules of our drug-design workflow currently amenable to replacement by QC: non-intuitively, we identify the mutation-impact predictor as the best candidate. HypaCADD thus combines classical docking and molecular dynamics with quantum machine learning (QML) to infer the impact of mutations. We present a case study with the coronavirus (SARS-CoV-2) protease and associated mutants. We map a classical machine-learning module onto QC, using a neural network constructed from qubit-rotation gates. We have implemented this in simulation and on two commercial quantum computers. We find that the QML models can perform on par with, if not better than, classical baselines. In summary, HypaCADD offers a successful strategy for leveraging QC for CADD. AVAILABILITY AND IMPLEMENTATION: Jupyter Notebooks with Python code are freely available for academic use on GitHub: https://www.github.com/hypahub/hypacadd_notebook. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
COVID-19 , Software , Humanos , Fluxo de Trabalho , Metodologias Computacionais , Teoria Quântica , SARS-CoV-2 , Desenho de Fármacos , Simulação de Dinâmica MolecularRESUMO
Ki67, a nuclear proliferation-related protein, is heavily used in anatomic pathology but has not become a companion diagnostic or a standard-of-care biomarker due to analytic variability in both assay protocols and interpretation. The International Ki67 Working Group in breast cancer has published and has ongoing efforts in the standardization of the interpretation of Ki67, but they have not yet assessed technical issues of assay production representing multiple sources of variation, including antibody clones, antibody formats, staining platforms, and operators. The goal of this work is to address these issues with a new standardization tool. We have developed a cell line microarray system in which mixes of human Karpas 299 or Jurkat cells (Ki67+) with Sf9 (Spodoptera frugiperda) (Ki67-) cells are present in incremental standardized ratios. To validate the tool, six different antibodies, including both ready-to-use and concentrate formats from six vendors, were used to measure Ki67 proliferation indices using IHC protocols for manual (bench-top) and automated platforms. The assays were performed by three different laboratories at Yale and analyzed using two image analysis software packages, including QuPath and Visiopharm. Results showed statistically significant differences in Ki67 reactivity between each antibody clone. However, subsets of Ki67 assays using three clones performed in three different labs show no significant differences. This work shows the need for analytic standardization of the Ki67 assay and provides a new tool to do so. We show here how a cell line standardization system can be used to normalize the staining variability in proliferation indices between different antibody clones in a triple negative breast cancer cohort. We believe that this cell line standardization array has the potential to improve reproducibility among Ki67 assays and laboratories, which is critical for establishing Ki67 as a standard-of-care assay.
Assuntos
Biomarcadores Tumorais/análise , Imuno-Histoquímica/normas , Antígeno Ki-67/análise , Índice Mitótico/normas , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Coregulation of the expression of groups of genes has been extensively demonstrated empirically in bacterial and eukaryotic systems. Such coregulation can arise through the use of shared regulatory motifs, which allow the coordinated expression of modules (and module groups) of functionally related genes across the genome. Coregulation can also arise through the physical association of multi-gene complexes through chromosomal looping, which are then transcribed together. We present a general formalism for modeling coregulation rules in the framework of Random Boolean Networks (RBN), and develop specific models for transcription factor networks with modular structure (including module groups, and multi-input modules (MIM) with autoregulation) and multi-gene complexes (including hierarchical differentiation between multi-gene complex members). We develop a mean-field approach to analyse the dynamical stability of large networks incorporating coregulation, and show that autoregulated MIM and hierarchical gene-complex models can achieve greater stability than networks without coregulation whose rules have matching activation frequency. We provide further analysis of the stability of small networks of both kinds through simulations. We also characterize several general properties of the transients and attractors in the hierarchical coregulation model, and show using simulations that the steady-state distribution factorizes hierarchically as a Bayesian network in a Markov Jump Process analogue of the RBN model.
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Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Modelos Genéticos , Teorema de Bayes , Simulação por Computador , Cadeias de MarkovRESUMO
Cultural processes of change bear many resemblances to biological evolution. The underlying units of non-biological evolution have, however, remained elusive, especially in the domain of music. Here, we introduce a general framework to jointly identify underlying units and their associated evolutionary processes. We model musical styles and principles of organization in dimensions such as harmony and form as following an evolutionary process. Furthermore, we propose that such processes can be identified by extracting latent evolutionary signatures from musical corpora, analogously to identifying mutational signatures in genomics. These signatures provide a latent embedding for each song or musical piece. We develop a deep generative architecture for our model, which can be viewed as a type of variational autoencoder with an evolutionary prior constraining the latent space; specifically, the embeddings for each song are tied together via an energy-based prior, which encourages songs close in evolutionary space to share similar representations. As illustration, we analyse songs from the McGill Billboard dataset. We find frequent chord transitions and formal repetition schemes and identify latent evolutionary signatures related to these features. Finally, we show that the latent evolutionary representations learned by our model outperform non-evolutionary representations in such tasks as period and genre prediction.
Assuntos
Evolução Cultural , Música , GenômicaRESUMO
PURPOSE: We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment. EXPERIMENTAL DESIGN: We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification. RESULTS: We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment. CONCLUSIONS: We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Melanoma , Transcriptoma , Microambiente Tumoral , Humanos , Melanoma/genética , Melanoma/terapia , Melanoma/imunologia , Melanoma/patologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Regulação Neoplásica da Expressão Gênica , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos CD/genética , Feminino , Masculino , Prognóstico , Macrófagos/imunologia , Macrófagos/metabolismo , Molécula CD68RESUMO
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
RESUMO
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
Assuntos
Encéfalo , Redes Reguladoras de Genes , Transtornos Mentais , Análise de Célula Única , Humanos , Envelhecimento/genética , Encéfalo/metabolismo , Comunicação Celular/genética , Cromatina/metabolismo , Cromatina/genética , Genômica , Transtornos Mentais/genética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Locos de Características QuantitativasRESUMO
For the COVID-19 pandemic, viral transmission has been documented in many historical and geographical contexts. Nevertheless, few studies have explicitly modeled the spatiotemporal flow based on genetic sequences, to develop mitigation strategies. Additionally, thousands of SARS-CoV-2 genomes have been sequenced with associated records, potentially providing a rich source for such spatiotemporal analysis, an unprecedented amount during a single outbreak. Here, in a case study of seven states, we model the first wave of the outbreak by determining regional connectivity from phylogenetic sequence information (i.e. "genetic connectivity"), in addition to traditional epidemiologic and demographic parameters. Our study shows nearly all of the initial outbreak can be traced to a few lineages, rather than disconnected outbreaks, indicative of a mostly continuous initial viral flow. While the geographic distance from hotspots is initially important in the modeling, genetic connectivity becomes increasingly significant later in the first wave. Moreover, our model predicts that isolated local strategies (e.g. relying on herd immunity) can negatively impact neighboring regions, suggesting more efficient mitigation is possible with unified, cross-border interventions. Finally, our results suggest that a few targeted interventions based on connectivity can have an effect similar to that of an overall lockdown. They also suggest that while successful lockdowns are very effective in mitigating an outbreak, less disciplined lockdowns quickly decrease in effectiveness. Our study provides a framework for combining phylodynamic and computational methods to identify targeted interventions.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2/genética , Pandemias/prevenção & controle , Filogenia , Controle de Doenças Transmissíveis/métodos , Surtos de DoençasRESUMO
Advances in single-cell RNA sequencing have allowed for the identification of cellular subtypes on the basis of quantification of the number of transcripts in each cell. However, cells might also differ in the spatial distribution of molecules, including RNAs. Here, we present DypFISH, an approach to quantitatively investigate the subcellular localization of RNA and protein. We introduce a range of analytical techniques to interrogate single-molecule RNA fluorescence in situ hybridization (smFISH) data in combination with protein immunolabeling. DypFISH is suited to study patterns of clustering of molecules, the association of mRNA-protein subcellular localization with microtubule organizing center orientation, and interdependence of mRNA-protein spatial distributions. We showcase how our analytical tools can achieve biological insights by utilizing cell micropatterning to constrain cellular architecture, which leads to reduction in subcellular mRNA distribution variation, allowing for the characterization of their localization patterns. Furthermore, we show that our method can be applied to physiological systems such as skeletal muscle fibers.
Assuntos
Fibras Musculares Esqueléticas , RNA , RNA/genética , Hibridização in Situ Fluorescente/métodos , RNA Mensageiro/genética , Fibras Musculares Esqueléticas/metabolismo , Transporte ProteicoRESUMO
Tumors accumulate thousands of mutations, and sequencing them has given rise to methods for finding cancer drivers via mutational recurrence. However, these methods require large cohorts and underperform for low recurrence. Recently, ultra-deep sequencing has enabled accurate measurement of VAFs (variant-allele frequencies) for mutations, allowing the determination of evolutionary trajectories. Here, based solely on the VAF spectrum for an individual sample, we report on a method that identifies drivers and quantifies tumor growth. Drivers introduce perturbations into the spectrum, and our method uses the frequency of hitchhiking mutations preceding a driver to measure this. As validation, we use simulation models and 993 tumors from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium with previously identified drivers. Then we apply our method to an ultra-deep sequenced acute myeloid leukemia (AML) tumor and identify known cancer genes and additional driver candidates. In summary, our framework presents opportunities for personalized driver diagnosis using sequencing data from a single individual.
Assuntos
Genes Supressores de Tumor , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Modelos Genéticos , Mutação , Algoritmos , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Taxa de Mutação , Mutação de Sentido Incorreto , Neoplasias/genética , Neoplasias/patologia , Oncogenes , Medicina de Precisão , Processos EstocásticosRESUMO
ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.
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Bases de Dados Genéticas , Genômica , Neoplasias/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Redes Reguladoras de Genes , Humanos , Mutação/genética , Reprodutibilidade dos Testes , Fatores de Transcrição/metabolismoRESUMO
Small RNA sequencing has been widely adopted to study the diversity of extracellular RNAs (exRNAs) in biofluids; however, the analysis of exRNA samples can be challenging: they are vulnerable to contamination and artifacts from different isolation techniques, present in lower concentrations than cellular RNA, and occasionally of exogenous origin. To address these challenges, we present exceRpt, the exRNA-processing toolkit of the NIH Extracellular RNA Communication Consortium (ERCC). exceRpt is structured as a cascade of filters and quantifications prioritized based on one's confidence in a given set of annotated RNAs. It generates quality control reports and abundance estimates for RNA biotypes. It is also capable of characterizing mappings to exogenous genomes, which, in turn, can be used to generate phylogenetic trees. exceRpt has been used to uniformly process all â¼3,500 exRNA-seq datasets in the public exRNA Atlas and is available from genboree.org and github.gersteinlab.org/exceRpt.
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Ácidos Nucleicos Livres/química , RNA-Seq/métodos , Software , Animais , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/metabolismo , Humanos , Camundongos , RNA-Seq/normasRESUMO
Face recognition algorithms perform very unreliably when the pose of the probe face is different from the gallery face: typical feature vectors vary more with pose than with identity. We propose a generative model that creates a one-to-many mapping from an idealized "identity" space to the observed data space. In identity space, the representation for each individual does not vary with pose. We model the measured feature vector as being generated by a pose-contingent linear transformation of the identity variable in the presence of Gaussian noise. We term this model "tied" factor analysis. The choice of linear transformation (factors) depends on the pose, but the loadings are constant (tied) for a given individual. We use the EM algorithm to estimate the linear transformations and the noise parameters from training data. We propose a probabilistic distance metric which allows a full posterior over possible matches to be established. We introduce a novel feature extraction process and investigate recognition performance using the FERET, XM2VTS and PIE databases. Recognition performance compares favourably to contemporary approaches.
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Inteligência Artificial , Biometria/métodos , Face/anatomia & histologia , Expressão Facial , Interpretação de Imagem Assistida por Computador/métodos , Reconhecimento Automatizado de Padrão/métodos , Técnica de Subtração , Algoritmos , Análise Fatorial , Humanos , Aumento da Imagem/métodos , Funções Verossimilhança , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.
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Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Predisposição Genética para Doença , Splicing de RNA , Esquizofrenia/genética , Encéfalo/metabolismo , Humanos , Isoformas de Proteínas/genética , Análise de Sequência de RNA , TranscriptomaRESUMO
Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.
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Encéfalo/metabolismo , Regulação da Expressão Gênica , Transtornos Mentais/genética , Conjuntos de Dados como Assunto , Aprendizado Profundo , Elementos Facilitadores Genéticos , Epigênese Genética , Epigenômica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas , Análise de Célula Única , TranscriptomaRESUMO
BACKGROUND: Although rapid diagnostic tests (RDTs) have practical advantages over light microscopy (LM) and good sensitivity in severe falciparum malaria in Africa, their utility where severe non-falciparum malaria occurs is unknown. LM, RDTs and polymerase chain reaction (PCR)-based methods have limitations, and thus conventional comparative malaria diagnostic studies employ imperfect gold standards. We assessed whether, using Bayesian latent class models (LCMs) which do not require a reference method, RDTs could safely direct initial anti-infective therapy in severe ill children from an area of hyperendemic transmission of both Plasmodium falciparum and P. vivax. METHODS AND FINDINGS: We studied 797 Papua New Guinean children hospitalized with well-characterized severe illness for whom LM, RDT and nested PCR (nPCR) results were available. For any severe malaria, the estimated prevalence was 47.5% with RDTs exhibiting similar sensitivity and negative predictive value (NPV) to nPCR (≥96.0%). LM was the least sensitive test (87.4%) and had the lowest NPV (89.7%), but had the highest specificity (99.1%) and positive predictive value (98.9%). For severe falciparum malaria (prevalence 42.9%), the findings were similar. For non-falciparum severe malaria (prevalence 6.9%), no test had the WHO-recommended sensitivity and specificity of >95% and >90%, respectively. RDTs were the least sensitive (69.6%) and had the lowest NPV (96.7%). CONCLUSIONS: RDTs appear a valuable point-of-care test that is at least equivalent to LM in diagnosing severe falciparum malaria in this epidemiologic situation. None of the tests had the required sensitivity/specificity for severe non-falciparum malaria but the number of false-negative RDTs in this group was small.
Assuntos
Testes Imunológicos , Malária/diagnóstico , Plasmodium falciparum/imunologia , Plasmodium vivax/imunologia , Antígenos de Protozoários/imunologia , Teorema de Bayes , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Cadeias de Markov , Método de Monte Carlo , Papua Nova Guiné , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking. METHODS AND FINDINGS: We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%). The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P=0.001); one child died (3.7%). The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P=0.003 vs falciparum malaria). Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO). CONCLUSIONS: The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis.