• Automated fetal heart rate analysis in labor: Decelerations and overshoots

    12 February 2018

    Electronic fetal heart rate (FHR) recording is a standard way of monitoring fetal health in labor. Decelerations and accelerations usually indicate fetal distress and normality respectively. But one type of acceleration may differ, namely an overshoot that may atypically reflect fetal stress. Here we describe a new method for detecting decelerations, accelerations and overshoots as part of a novel system for computerized FHR analysis (OxSyS). There was poor agreement between clinicians when identifying these FHR features visually, which precluded setting a gold standard of interpretation. We therefore introduced 'modified' Sensitivity (SE°) and 'modified' Positive Predictive Value (PPV°) as appropriate performance measures with which the algorithm was optimized. The relation between overshoots and fetal compromise in labor was studied in 15 cases and 15 controls. Overshoots showed promise as an indicator of fetal compromise. Unlike ordinary accelerations, overshoots cannot be considered to be reassuring features of fetal health. © 2010 American Institute of Physics.

  • Umbilical cord gases in relation to the neonatal condition: The EveREst plot

    12 February 2018

    Objective: To validate umbilical arterial and venous pH and base deficit (pH UA , pH UV , BD UA , and BD UV , respectively), as well as venous-arterial pH differences, as measures of perinatal condition at birth (in relation to emergency intervention, resuscitation, facial mask, low Apgar, seizures, other cerebral problems or death); to investigate whether BD UA or pH UA better measures perinatal risk. Study design: A novel method (Event Rate Estimate (EveREst) plots) was used to analyze cord blood gases and perinatal outcomes of 34,510 term singleton deliveries: cord blood gas values were grouped into exclusive quantiles (containing equal proportions of cases); the quantiles were plotted against per cent rates (event rates) for perinatal outcomes; the event rates for the different blood gases were compared using the χ 2 test for difference of proportions. Results: Low pH UA predicts poor perinatal outcome better than or comparably to high BD UA : pH UA is significantly better than BD UA for predicting low Apgar, resuscitation and facial mask (p < 0.001, p < 0.05, and p < 0.001, respectively). For seizures and other cerebral problems, low pH UA is better than high BD UA but the difference is not statistically significant. For death, both measures perform equally well. Interventions for the specific reason of "fetal distress" increased as pH UA decreased but only where electronic fetal monitoring was used. In acidemic neonates (pH UA ≤ 7.05, n = 1752), significantly more cord prolapses and placenta abruptions were associated with large and small venous-arterial pH difference (pH VAD ) respectively (p < 0.01). Conclusion: EveREst plots display clearly the diagnostic value of cord gases. They allow for the easy identification of background rates and increases above background, thresholds of interest, and comparison of the blood gas measures. Overall pH UA is the best umbilical blood measure of perinatal outcome. BD UA is comparable or inferior. Extremes of pH VAD (large or small) identify higher proportions of specific poor outcomes in acidemic neonates. © 2013 Elsevier Ireland Ltd.

  • Artificial neural networks applied to fetal monitoring in labour

    3 April 2018

    Birth asphyxia can result in death or permanent brain damage. To prevent it, the fetal heart rate (FHR) is recorded in labour on a paper strip. In clinical practice, the complicated FHR patterns are assessed by eye, which is error-prone, inconsistent and unreliable. Objective alternatives are needed and thus we investigated the applicability of feed-forward artificial neural networks (ANNs) for FHR analysis. Six FHR features were extracted and combined with six clinical parameters to form a feature space of 12 dimensions. The feature space was reduced to six dimensions by principal component analysis. Subsequently, a network committee of ten ANNs was trained with the data of 124 patients (a balanced set of 62 adverse, coded 1, and 62 normal outcomes, coded 0). The ANN committee was tested on another balanced set of 252 patients obtaining misclassification rate of 36%. Finally, the committee was tested on a large dataset of 7,568 patients (non-balanced). As the committee output continuously increased from 0 to 1, there was a consistent growth of the adverse outcome rate (from 0.26 to 5.3%) and the low umbilical pH rate (from 2.6 to 16.7%.) Based on this correlation between the committee output and the risk of compromise, we concluded that ANNs can be successfully applied to FHR monitoring in labour. However, extensive further work is necessary, for which we outline our plans. To our knowledge, this is the first time that an automated method for FHR diagnostic analysis has been tested on a database of this size. © 2011 Springer-Verlag London Limited.

  • Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe.

    15 March 2018

    HIV-1 set-point viral load-the approximately stable value of viraemia in the first years of chronic infection-is a strong predictor of clinical outcome and is highly variable across infected individuals. To better understand HIV-1 pathogenesis and the evolution of the viral population, we must quantify the heritability of set-point viral load, which is the fraction of variation in this phenotype attributable to viral genetic variation. However, current estimates of heritability vary widely, from 6% to 59%. Here we used a dataset of 2,028 seroconverters infected between 1985 and 2013 from 5 European countries (Belgium, Switzerland, France, the Netherlands and the United Kingdom) and estimated the heritability of set-point viral load at 31% (CI 15%-43%). Specifically, heritability was measured using models of character evolution describing how viral load evolves on the phylogeny of whole-genome viral sequences. In contrast to previous studies, (i) we measured viral loads using standardized assays on a sample collected in a strict time window of 6 to 24 months after infection, from which the viral genome was also sequenced; (ii) we compared 2 models of character evolution, the classical "Brownian motion" model and another model ("Ornstein-Uhlenbeck") that includes stabilising selection on viral load; (iii) we controlled for covariates, including age and sex, which may inflate estimates of heritability; and (iv) we developed a goodness of fit test based on the correlation of viral loads in cherries of the phylogenetic tree, showing that both models of character evolution fit the data well. An overall heritability of 31% (CI 15%-43%) is consistent with other studies based on regression of viral load in donor-recipient pairs. Thus, about a third of variation in HIV-1 virulence is attributable to viral genetic variation.

  • Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination.

    3 April 2018

    Diversity of the polysaccharide capsule in Streptococcus pneumoniae-main surface antigen and the target of the currently used pneumococcal vaccines-constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium's ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination.

  • Genomic epidemiology reveals multiple introductions of Zika virus into the United States.

    3 April 2018

    Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016-several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions.