Fast algorithms for computing sequence distances by exhaustive substring composition

The increasing throughput of sequencing raises growing needs for methods of sequence analysis and comparison on a genomic scale, notably, in connection with phylogenetic tree reconstruction. Such needs are hardly fulfilled by the more traditional measures of sequence similarity and distance, like string edit and gene rearrangement, due to a mixture of epistemological and computational problems. Alternative measures, based on the subword composition of sequences, have emerged in recent years and proved to be both fast and effective in a variety of tested cases. The common denominator of such measures is an underlying information theoretic notion of relative compressibility. Their viability depends critically on computational cost. The present paper describes as a paradigm the extension and efficient implementation of one of the methods in this class. The method is based on the comparison of the frequencies of all subwords in the two input sequences, where frequencies are suitably adjusted to take into account the statistical background

Efficient representation of uncertainty in multiple sequence alignments using directed acyclic graphs

Background A standard procedure in many areas of bioinformatics is to use a single multiple sequence alignment (MSA) as the basis for various types of analysis. However, downstream results may be highly sensitive to the alignment used, and neglecting the uncertainty in the alignment can lead to significant bias in the resulting inference. In recent years, a number of approaches have been developed for probabilistic sampling of alignments, rather than simply generating a single optimum. However, this type of probabilistic information is currently not widely used in the context of downstream inference, since most existing algorithms are set up to make use of a single alignment. Results In this work we present a framework for representing a set of sampled alignments as a directed acyclic graph (DAG) whose nodes are alignment columns; each path through this DAG then represents a valid alignment. Since the probabilities of individual columns can be estimated from empirical frequencies, this approach enables sample-based estimation of posterior alignment probabilities. Moreover, due to conditional independencies between columns, the graph structure encodes a much larger set of alignments than the original set of sampled MSAs, such that the effective sample size is greatly increased. Conclusions The alignment DAG provides a natural way to represent a distribution in the space of MSAs, and allows for existing algorithms to be efficiently scaled up to operate on large sets of alignments. As an example, we show how this can be used to compute marginal probabilities for tree topologies, averaging over a very large number of MSAs. This framework can also be used to generate a statistically meaningful summary alignment; example applications show that this summary alignment is consistently more accurate than the majority of the alignment samples, leading to improvements in downstream tree inference. Implementations of the methods described in this article are available at http://statalign.github.io/WeaveAlign webcite

Organizational Heterogeneity of Vertebrate Genomes

Genomes of higher eukaryotes are mosaics of segments with various structural, functional, and evolutionary properties. The availability of whole-genome sequences allows the investigation of their structure as “texts” using different statistical and computational methods. One such method, referred to as Compositional Spectra (CS) analysis, is based on scoring the occurrences of fixed-length oligonucleotides (k-mers) in the target DNA sequence. CS analysis allows generating species- or region-specific characteristics of the genome, regardless of their length and the presence of coding DNA. In this study, we consider the heterogeneity of vertebrate genomes as a joint effect of regional variation in sequence organization superimposed on the differences in nucleotide composition. We estimated compositional and organizational heterogeneity of genome and chromosome sequences separately and found that both heterogeneity types vary widely among genomes as well as among chromosomes in all investigated taxonomic groups. The high correspondence of heterogeneity scores obtained on three genome fractions, coding, repetitive, and the remaining part of the noncoding DNA (the genome dark matter - GDM) allows the assumption that CS-heterogeneity may have functional relevance to genome regulation. Of special interest for such interpretation is the fact that natural GDM sequences display the highest deviation from the corresponding reshuffled sequences

Calculated initial parenteral treatment of bacterial infections: Sepsis

This is the eleventh chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.Sepsis, defined as a life threatening organ dysfunction caused by a misregulated host response to an infection, is the third leading cause of death in Germany with a lethality rate of 30% to over 50%. An early, effective antimicrobial therapy is, next to infectious source control, the most important causal treatment option. It should be complemented by the mainly supportive measures of general intensive care therapy. Prior antimicrobial therapy, the patient's medical history (e.g. risk factors for multiresistant agents) and small-scale epidemiology are to be considered as part of the therapeutic and practical decisions. A modification of the often needed broad initial calculated combination therapy is desirable. In the future, prompt measurements of plasma concentrations of antiinfectives, especially for the sepsis patient with diverse and partly conflicting pathophysiological changes, will have great importance regarding efficacy, toxicity and resistance development. In order to apply those complex strategies in clinical routine, there is a requirement for a strong interdisciplinary collaboration between the intensive care unit, clinical infectiology, microbiology, and clinical pharmacology, ideally in the framework of a functional antimicrobial stewardship program.Dies ist das elfte Kapitel der von der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie "Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen - Update 2018" in der 2. aktualisierten Fassung.Sepsis als die dritthäufigste Todesursache in Deutschland mit einer Letalität von 30 bis über 50% ist definiert als lebensbedrohliche Organdysfunktion, die durch eine fehlregulierte Wirtsantwort auf eine Infektion hervorgerufen wird. Die frühe, wirksame antimikrobielle Therapie stellt neben der Fokussanierung/-kontrolle die wichtigste kausale Behandlungsoption dar, ergänzt durch die allgemeine Intensivtherapie mit ihren vor allem supportiven Maßnahmen. Eine antimikrobielle Vortherapie, die Vorgeschichte des Patienten (z.B. Risikofaktoren für multiresistente Erreger) und die Kleinraumepidemiologie sollten unbedingt in die therapeutischen und praktischen Erwägungen einbezogen werden. Eine Modifizierung der zunächst oft breit notwendigen kalkulierten Kombinationstherapie ist anzustreben. In Zukunft wird der zeitnahen Plasmakonzentrationsbestimmung von Antiinfektiva gerade beim Sepsis-Patienten mit seinen vielfältigen, teils gegenläufigen pathophysiologischen Veränderungen eine herausragende Bedeutung im Hinblick auf Wirksamkeit, Toxizität und Resistenzentwicklung zukommen. Um diese komplexen Strategien im klinischen Alltag erfolgreich umsetzen zu können, bedarf es der engen Zusammenarbeit des Intensivmediziners/Klinikers mit der klinischen Infektiologie, der Mikrobiologie und der klinischen Pharmakologie, idealerweise im Rahmen eines funktionierenden Antimicrobial Stewardship Programmes