Small All-Range Lidar for Asteroid and Comet Core Missions.

We report the development of a new type of space lidar specifically designed for missions to small planetary bodies for both topographic mapping and support of sample collection or landing. The instrument is designed to have a wide dynamic range with several operation modes for different mission phases. The laser transmitter consists of a fiber laser that is intensity modulated with a return-to-zero pseudo-noise (RZPN) code. The receiver detects the coded pulse-train by correlating the detected signal with the RZPN kernel. Unlike regular pseudo noise (PN) lidars, the RZPN kernel is set to zero outside laser firing windows, which removes most of the background noise over the receiver integration time. This technique enables the use of low peak-power but high pulse-rate lasers, such as fiber lasers, for long-distance ranging without aliasing. The laser power and the internal gain of the detector can both be adjusted to give a wide measurement dynamic range. The laser modulation code pattern can also be reconfigured in orbit to optimize measurements to different measurement environments. The receiver uses a multi-pixel linear mode photon-counting HgCdTe avalanche photodiode (APD) array with near quantum limited sensitivity at near to mid infrared wavelengths where many fiber lasers and diode lasers operate. The instrument is modular and versatile and can be built mostly with components developed by the optical communication industry.

Machine Learning Approaches to Determine Feature Importance for Predicting Infant Autopsy Outcome.

INTRODUCTION: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of postneonatal death. We explored whether machine learning could be used to derive data driven insights for prediction of infant autopsy outcome. METHODS: A paediatric autopsy database containing >7,000 cases, with >300 variables, was analysed by examination stage and autopsy outcome classified as 'explained (medical cause of death identified)' or 'unexplained'. Decision tree, random forest, and gradient boosting models were iteratively trained and evaluated. RESULTS: Data from 3,100 infant and young child (<2 years) autopsies were included. Naïve decision tree using external examination data had performance of 68% for predicting an explained death. Core data items were identified using model feature importance. The most effective model was XG Boost, with overall predictive performance of 80%, demonstrating age at death, and cardiovascular and respiratory histological findings as the most important variables associated with determining medical cause of death. CONCLUSION: This study demonstrates feasibility of using machine-learning to evaluate component importance of complex medical procedures (paediatric autopsy) and highlights value of collecting routine clinical data according to defined standards. This approach can be applied to a range of clinical and operational healthcare scenarios.

Using offsets to mitigate environmental impacts of major projects: A stakeholder analysis.

Global patterns of development suggest that as more projects are initiated, business will need to find acceptable measures to conserve biodiversity. The application of environmental offsets allows firms to combine their economic interests with the environment and society. This article presents the results of a multi-stakeholder analysis related to the design of offsets principles, policies, and regulatory processes, using a large infrastructure projects context. The results indicate that business was primarily interested in using direct offsets and other compensatory measures, known internationally as indirect offsets, to acquit their environmental management obligations. In contrast, the environmental sector argued that highly principled and scientifically robust offsets programs should be implemented and maintained for enduring environmental protection. Stakeholder consensus stressed the importance of offsets registers with commensurate monitoring and enforcement. Our findings provide instructive insights into the countervailing views of offsets policy stakeholders.

Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences.

Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online 'TB-Profiler' tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

A robust SNP barcode for typing Mycobacterium tuberculosis complex strains.

Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify ~92 k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the ~7 k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type.

PolyTB: a genomic variation map for Mycobacterium tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second major cause of death from an infectious disease worldwide. Recent advances in DNA sequencing are leading to the ability to generate whole genome information in clinical isolates of M. tuberculosis complex (MTBC). The identification of informative genetic variants such as phylogenetic markers and those associated with drug resistance or virulence will help barcode Mtb in the context of epidemiological, diagnostic and clinical studies. Mtb genomic datasets are increasingly available as raw sequences, which are potentially difficult and computer intensive to process, and compare across studies. Here we have processed the raw sequence data (>1500 isolates, eight studies) to compile a catalogue of SNPs (n = 74,039, 63% non-synonymous, 51.1% in more than one isolate, i.e. non-private), small indels (n = 4810) and larger structural variants (n = 800). We have developed the PolyTB web-based tool (http://pathogenseq.lshtm.ac.uk/polytb) to visualise the resulting variation and important meta-data (e.g. in silico inferred strain-types, location) within geographical map and phylogenetic views. This resource will allow researchers to identify polymorphisms within candidate genes of interest, as well as examine the genomic diversity and distribution of strains. PolyTB source code is freely available to researchers wishing to develop similar tools for their pathogen of interest.

SpolPred: rapid and accurate prediction of Mycobacterium tuberculosis spoligotypes from short genomic sequences.

SUMMARY: Spoligotyping is a well-established genotyping technique based on the presence of unique DNA sequences in Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis disease (TB). Although advances in sequencing technologies are leading to whole-genome bacterial characterization, tens of thousands of isolates have been spoligotyped, giving a global view of Mtb strain diversity. To bridge the gap, we have developed SpolPred, a software to predict the spoligotype from raw sequence reads. Our approach is compared with experimentally and de novo assembly determined strain types in a set of 44 Mtb isolates. In silico and experimental results are identical for almost all isolates (39/44). However, SpolPred detected five experimentally false spoligotypes and was more accurate and faster than the assembling strategy. Application of SpolPred to an additional seven isolates with no laboratory data led to types that clustered with identical experimental types in a phylogenetic analysis using single-nucleotide polymorphisms. Our results demonstrate the usefulness of the tool and its role in revealing experimental limitations. AVAILABILITY AND IMPLEMENTATION: SpolPred is written in C and is available from www.pathogenseq.org/spolpred. CONTACT: francesc.coll@lshtm.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics Online.

ISPIDER Central: an integrated database web-server for proteomics.

Despite the growing volumes of proteomic data, integration of the underlying results remains problematic owing to differences in formats, data captured, protein accessions and services available from the individual repositories. To address this, we present the ISPIDER Central Proteomic Database search (http://www.ispider.manchester.ac.uk/cgi-bin/ProteomicSearch.pl), an integration service offering novel search capabilities over leading, mature, proteomic repositories including PRoteomics IDEntifications database (PRIDE), PepSeeker, PeptideAtlas and the Global Proteome Machine. It enables users to search for proteins and peptides that have been characterised in mass spectrometry-based proteomics experiments from different groups, stored in different databases, and view the collated results with specialist viewers/clients. In order to overcome limitations imposed by the great variability in protein accessions used by individual laboratories, the European Bioinformatics Institute's Protein Identifier Cross-Reference (PICR) service is used to resolve accessions from different sequence repositories. Custom-built clients allow users to view peptide/protein identifications in different contexts from multiple experiments and repositories, as well as integration with the Dasty2 client supporting any annotations available from Distributed Annotation System servers. Further information on the protein hits may also be added via external web services able to take a protein as input. This web server offers the first truly integrated access to proteomics repositories and provides a unique service to biologists interested in mass spectrometry-based proteomics.

Gene3D: comprehensive structural and functional annotation of genomes.

Gene3D provides comprehensive structural and functional annotation of most available protein sequences, including the UniProt, RefSeq and Integr8 resources. The main structural annotation is generated through scanning these sequences against the CATH structural domain database profile-HMM library. CATH is a database of manually derived PDB-based structural domains, placed within a hierarchy reflecting topology, homology and conservation and is able to infer more ancient and divergent homology relationships than sequence-based approaches. This data is supplemented with Pfam-A, other non-domain structural predictions (i.e. coiled coils) and experimental data from UniProt. In order to enhance the investigations possible with this data, we have also incorporated a variety of protein annotation resources, including protein-protein interaction data, GO functional assignments, KEGG pathways, FUNCAT functional descriptions and links to microarray expression data. All of this data can be accessed through a newly re-designed website that has a focus on flexibility and clarity, with searches that can be restricted to a single genome or across the entire sequence database. Currently Gene3D contains over 3.5 million domain assignments for nearly 5 million proteins including 527 completed genomes. This is available at: http://gene3d.biochem.ucl.ac.uk/

Consensus clustering and functional interpretation of gene-expression data.

Microarray analysis using clustering algorithms can suffer from lack of inter-method consistency in assigning related gene-expression profiles to clusters. Obtaining a consensus set of clusters from a number of clustering methods should improve confidence in gene-expression analysis. Here we introduce consensus clustering, which provides such an advantage. When coupled with a statistically based gene functional analysis, our method allowed the identification of novel genes regulated by NFkappaB and the unfolded protein response in certain B-cell lymphomas.

PFDB: a generic protein family database integrating the CATH domain structure database with sequence based protein family resources.

MOTIVATION: The PFDB (Protein Family Database) is a new database designed to integrate protein family-related data with relevant functional and genomic data. It currently manages biological data for three projects-the CATH protein domain database (Orengo et al., 1997; Pearl et al., 2001), the VIDA virus domains database (Albà et al., 2001) and the Gene3D database (Buchan et al., 2001). The PFDB has been designed to accommodate protein families identified by a variety of sequence based or structure based protocols and provides a generic resource for biological research by enabling mapping between different protein families and diverse biochemical and genetic data, including complete genomes. RESULTS: A characteristic feature of the PFDB is that it has a number of meta-level entities (for example aggregation, collection and inclusion) represented as base tables in the final design. The explicit representation of relationships at the meta-level has a number of advantages, including flexibility-both in terms of the range of queries that can be formulated and the ability to integrate new biological entities within the existing design. A potential drawback with this approach-poor performance caused by the number of joins across meta-level tables-is avoided by implementing the PFDB with materialized views using the mature relational database technology of Oracle 8i. The resultant database is both fast and flexible. This paper presents the principles on which the database has been designed and implemented, and describes the current status of the database and query facilities supported.