COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project

Background

With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result.

Results

We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software.

Conclusions

The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0369-z) contains supplementary material, which is available to authorized users.     

The Eucalyptus terpene synthase gene family

Background

Terpenoids are abundant in the foliage of Eucalyptus, providing the characteristic smell as well as being valuable economically and influencing ecological interactions. Quantitative and qualitative inter- and intra- specific variation of terpenes is common in eucalypts.

Results

The genome sequences of Eucalyptus grandis and E. globulus were mined for terpene synthase genes (TPS) and compared to other plant species. We investigated the relative expression of TPS in seven plant tissues and functionally characterized five TPS genes from E. grandis. Compared to other sequenced plant genomes, Eucalyptus grandis has the largest number of putative functional TPS genes of any sequenced plant. We discovered 113 and 106 putative functional TPS genes in E. grandis and E. globulus, respectively. All but one TPS from E. grandis were expressed in at least one of seven plant tissues examined. Genomic clusters of up to 20 genes were identified. Many TPS are expressed in tissues other than leaves which invites a re-evaluation of the function of terpenes in Eucalyptus.

Conclusions

Our data indicate that terpenes in Eucalyptus may play a wider role in biotic and abiotic interactions than previously thought. Tissue specific expression is common and the possibility of stress induction needs further investigation. Phylogenetic comparison of the two investigated Eucalyptus species gives insight about recent evolution of different clades within the TPS gene family. While the majority of TPS genes occur in orthologous pairs some clades show evidence of recent gene duplication, as well as loss of function.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1598-x) contains supplementary material, which is available to authorized users.     

Automatic identification and characterization of radial files in light microscopy images of wood

Background and Aims

Analysis of anatomical sections of wood provides important information for understanding the secondary growth and development of plants. This study reports on a new method for the automatic detection and characterization of cell files in wood images obtained by light microscopy. To facilitate interpretation of the results, reliability coefficients have been determined, which characterize the files, their cells and their respective measurements.

Methods

Histological sections and blocks of the gymnosperms Pinus canariensis, P. nigra and Abies alba were used, together with histological sections of the angiosperm mahogany (Swietenia spp.). Samples were scanned microscopically and mosaic images were built up. After initial processing to reduce noise and enhance contrast, cells were identified using a ‘watershed’ algorithm and then cell files were built up by the successive aggregation of cells taken from progressively enlarged neighbouring regions. Cell characteristics such as thickness and size were calculated, and a method was developed to determine the reliability of the measurements relative to manual methods.

Key Results

Image analysis using this method can be performed in less than 20 s, which compares with a time of approx. 40 min to produce the same results manually. The results are accompanied by a reliability indicator that can highlight specific configurations of cells and also potentially erroneous data.

Conclusions

The method provides a fast, economical and reliable tool for the identification of cell files. The reliability indicator characterizing the files permits quick filtering of data for statistical analysis while also highlighting particular biological configurations present in the wood sections.     

A Monte Carlo study on dose distribution evaluation of Flexisource 192Ir brachytherapy source

Aim

The aim of this study is to evaluate the dose distribution of the Flexisource ¹⁹²Ir source.

Background

Dosimetric evaluation of brachytherapy sources is recommended by task group number 43 (TG. 43) of American Association of Physicists in Medicine (AAPM).

Materials and methods

MCNPX code was used to simulate Flexisource ¹⁹²Ir source. Dose rate constant and radial dose function were obtained for water and soft tissue phantoms and compared with previous data on this source. Furthermore, dose rate along the transverse axis was obtained by simulation of the Flexisource and a point source and the obtained data were compared with those from Flexiplan treatment planning system (TPS).

Results

The values of dose rate constant obtained for water and soft tissue phantoms were equal to 1.108 and 1.106, respectively. The values of the radial dose function are listed in the form of tabulated data. The values of dose rate (cGy/s) obtained are shown in the form of tabulated data and figures. The maximum difference between TPS and Monte Carlo (MC) dose rate values was 11% in a water phantom at 6.0 cm from the source.

Conclusion

Based on dosimetric parameter comparisons with values previously published, the accuracy of our simulation of Flexisource ¹⁹²Ir was verified. The results of dose rate constant and radial dose function in water and soft tissue phantoms were the same for Flexisource and point sources. For Flexisource ¹⁹²Ir source, the results of TPS calculations in a water phantom were in agreement with the simulations within the calculation uncertainties. Furthermore, the results from the TPS calculation for Flexisource and MC calculation for a point source were practically equal within the calculation uncertainties.     

An institutional experience of quality assurance of a treatment planning system on photon beam

Aim

The purpose of the present study is to show the application of the IAEA TRS-430 QA procedures of Eclipse™v7.5 TPS for photon energies. In addition, the trends of the deviations found in the conducted tests were determined.

Background

In the past, the lack of complete TPS QA procedures led to some serious accidents. So, QA in the radiotherapy treatment planning process is essential for determination of accuracy in the radiotherapy process and avoidance of treatment errors.

Materials and methods

The calculations of TPS and measurements of irradiations of the treatment device were compared in the study. As a result, the local dose deviation values (δ₁: central beam axis, δ₂: penumbra and build up region, δ₃: inside field, δ₄: outside beam edges, δ_50–90: beam fringe, RW₅₀: radiological width) and their confidence limit values (including systematic and random errors) were obtained.

Results

The confidence limit values of δ₄ were detected to increase with expanding field size. The values of δ₁ and δ₃ of hard wedge were larger than open fields. The values of δ₂ and δ_50–90 of the inhomogeneity effect test were larger, especially than other tests of this study. The average deviation was showed to increase with the rise of the wedge angle. The values of δ₃ and δ₄ of lung irradiation were outside tolerance.

Conclusions

The QA of TPS was done and it was found that there were no reservations in its use in patient treatment. The trend of the deviations is shown.     

Analyzing the performance of ArcCHECK diode array detector for VMAT plan

Aim

The aim of this study is to evaluate performance of ArcCHECK diode array detector for the volumetric modulated arc therapy (VMAT) patient specific quality assurance (QA). VMAT patient specific QA results were correlated with ion chamber measurement. Dose response of the ArcCHECK detector was studied.

Background

VMAT delivery technique improves the dose distribution. It is complex in nature and requires proper QA before its clinical implementation. ArcCHECK is a novel three dimensional dosimetry system.

Materials and methods

Twelve retrospective VMAT plans were calculated on ArcCHECK phantom. Point dose and dose map were measured simultaneously with ion chamber (IC-15) and ArcCHECK diode array detector, respectively. These measurements were compared with their respective TPS calculated values.

Results

The ion chamber measurements are in good agreement with TPS calculated doses. Mean difference between them is 0.50% with standard deviation of 0.51%. Concordance correlation coefficient (CCC) obtained for ion chamber measurements is 0.9996. These results demonstrate a strong correlation between the absolute dose predicted by our TPS and the measured dose. The CCC between ArcCHECK doses and TPS predictions on the CAX was found to be 0.9978. In gamma analysis of dose map, the mean passing rate was 98.53% for 3% dose difference and 3 mm distance to agreement.

Conclusions

The VMAT patient specific QA with an ion chamber and ArcCHECK phantom are consistent with the TPS calculated dose. Statistically good agreement was observed between ArcCHECK measured and TPS calculated. Hence, it can be used for routine VMAT QA.     

New System for Digital to Analog Transformation and Reconstruction of 12-Lead ECGs

Introduction

We describe initial validation of a new system for digital to analog conversion (DAC) and reconstruction of 12-lead ECGs. The system utilizes an open and optimized software format with a commensurately optimized DAC hardware configuration to accurately reproduce, from digital files, the original analog electrocardiographic signals of previously instrumented patients. By doing so, the system also ultimately allows for transmission of data collected on one manufacturer''s 12-lead ECG hardware/software into that of any other.

Materials and Methods

To initially validate the system, we compared original and post-DAC re-digitized 12-lead ECG data files (∼5-minutes long) in two types of validation studies in 10 patients. The first type quantitatively compared the total waveform voltage differences between the original and re-digitized data while the second type qualitatively compared the automated electrocardiographic diagnostic statements generated by the original versus re-digitized data.

Results

The grand-averaged difference in root mean squared voltage between the original and re-digitized data was 20.8 µV per channel when re-digitization involved the same manufacturer''s analog to digital converter (ADC) as the original digitization, and 28.4 µV per channel when it involved a different manufacturer''s ADC. Automated diagnostic statements generated by the original versus reconstructed data did not differ when using the diagnostic algorithm from the same manufacturer on whose device the original data were collected, and differed only slightly for just 1 of 10 patients when using a third-party diagnostic algorithm throughout.

Conclusion

Original analog 12-lead ECG signals can be reconstructed from digital data files with accuracy sufficient for clinical use. Such reconstructions can readily enable automated second opinions for difficult-to-interpret 12-lead ECGs, either locally or remotely through the use of dedicated or cloud-based servers.     

IM-TORNADO: A Tool for Comparison of 16S Reads from Paired-End Libraries

Motivation

16S rDNA hypervariable tag sequencing has become the de facto method for accessing microbial diversity. Illumina paired-end sequencing, which produces two separate reads for each DNA fragment, has become the platform of choice for this application. However, when the two reads do not overlap, existing computational pipelines analyze data from read separately and underutilize the information contained in the paired-end reads.

Results

We created a workflow known as Illinois Mayo Taxon Organization from RNA Dataset Operations (IM-TORNADO) for processing non-overlapping reads while retaining maximal information content. Using synthetic mock datasets, we show that the use of both reads produced answers with greater correlation to those from full length 16S rDNA when looking at taxonomy, phylogeny, and beta-diversity.

Availability and Implementation

IM-TORNADO is freely available at http://sourceforge.net/projects/imtornado and produces BIOM format output for cross compatibility with other pipelines such as QIIME, mothur, and phyloseq.     

A Monte Carlo study on dose distribution validation of GZP6 60Co stepping source

Aim

Stepping source in brachytherapy systems is used to treat a target lesion longer than the effective treatment length of the source. Cancerous lesions in the cervix, esophagus and rectum are examples of such a target lesion.

Background

In this study, the stepping source of a GZP6 afterloading intracavitary brachytherapy unit was simulated using Monte Carlo (MC) simulation and the results were used for the validation of the GZP6 treatment planning system (TPS).

Materials and methods

The stepping source was simulated using MCNPX Monte Carlo code. Dose distributions in the longitudinal plane were obtained by using a matrix shift method for esophageal tumor lengths of 8 and 10 cm. A mesh tally has been employed for the absorbed dose calculation in a cylindrical water phantom. A total of 5 × 10⁸ photon histories were scored and the MC statistical error obtained was at the range of 0.008–3.5%, an average of 0.2%.

Results

The acquired MC and TPS isodose curves were compared and it was shown that the dose distributions in the longitudinal plane were relatively coincidental. In the transverse direction, a maximum dose difference of 7% and 5% was observed for tumor lengths of 8 and 10 cm, respectively.

Conclusion

Considering that the certified source activity is given with ±10% uncertainty, the obtained difference is reasonable. It can be concluded that the accuracy of the dose distributions produced by GZP6 TPS for the stepping source is acceptable for its clinical applications.     

Effect of Transcranial Magnetic Stimulation (TMS) on Parietal and Premotor Cortex during Planning of Reaching Movements

Background

Cerebral activation during planning of reaching movements occurs both in the superior parietal lobule (SPL) and premotor cortex (PM), and their activation seems to take place in parallel.

Methodology

The activation of the SPL and PM has been investigated using transcranial magnetic stimulation (TMS) during planning of reaching movements under visual guidance.

Principal Findings

A facilitory effect was found when TMS was delivered on the parietal cortex at about half of the time from sight of the target to hand movement, independently of target location in space. Furthermore, at the same stimulation time, a similar facilitory effect was found in PM, which is probably related to movement preparation.

Conclusions

This data contributes to the understanding of cortical dynamics in the parieto-frontal network, and suggests that it is possible to interfere with the planning of reaching movements at different cortical points within a particular time window. Since similar effects may be produced at similar times on both the SPL and PM, parallel processing of visuomotor information is likely to take place in these regions.     

External validation of Adjuvant! Online breast cancer prognosis tool. Prioritising recommendations for improvement

Background

Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors.

Patients and Methods

The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction.

Results

Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old.

Conclusion

Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index.     

Geographically widespread swordfish barcode stock identification: a case study of its application

Background

The swordfish (Xiphias gladius) is a cosmopolitan large pelagic fish inhabiting tempered and tropical waters and it is a target species for fisheries all around the world. The present study investigated the ability of COI barcoding to reliably identify swordfish and particularly specific stocks of this commercially important species.

Methodology

We applied the classical DNA barcoding technology, upon a 682 bp segment of COI, and compared swordfish sequences from different geographical sources (Atlantic, Indian Oceans and Mediterranean Sea). The sequences of the 5′ hyper-variable fragment of the control region (5′dloop), were also used to validate the efficacy of COI as a stock-specific marker.

Case Report

This information was successfully applied to the discrimination of unknown samples from the market, detecting in some cases mislabeled seafood products.

Conclusions

The NJ distance-based phenogram (K2P model) obtained with COI sequences allowed us to correlate the swordfish haplotypes to the different geographical stocks. Similar results were obtained with 5′dloop. Our preliminary data in swordfish Xiphias gladius confirm that Cytochrome Oxidase I can be proposed as an efficient species-specific marker that has also the potential to assign geographical provenance. This information might speed the samples analysis in commercial application of barcoding.     

ANGSD: Analysis of Next Generation Sequencing Data

Background

High-throughput DNA sequencing technologies are generating vast amounts of data. Fast, flexible and memory efficient implementations are needed in order to facilitate analyses of thousands of samples simultaneously.

Results

We present a multithreaded program suite called ANGSD. This program can calculate various summary statistics, and perform association mapping and population genetic analyses utilizing the full information in next generation sequencing data by working directly on the raw sequencing data or by using genotype likelihoods.

Conclusions

The open source c/c++ program ANGSD is available at http://www.popgen.dk/angsd. The program is tested and validated on GNU/Linux systems. The program facilitates multiple input formats including BAM and imputed beagle genotype probability files. The program allow the user to choose between combinations of existing methods and can perform analysis that is not implemented elsewhere.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0356-4) contains supplementary material, which is available to authorized users.     

Wax boluses and accuracy of EBT and RTQA radiochromic film detectors in radiotherapy with the JINR Phasotron proton beam

Aim

To present the results obtained using radiochromic films EBT and RTQA 1010P for the reconstruction the dose distributions for targets irradiated by proton beam and modified by wax boluses.

Background

In Medico-Technical Complex at the Joint Institute for Nuclear Research in Dubna implemented technology of wax boluses.

Materials and methods

Wax boluses are easier to make and they give better dose distributions than boluses made from modeling clay previously used at our center. We irradiated two imaginary targets, one shaped as a cylinder and the other one as two cuboids. The evaluated calibration curve was used for calculation of the dose distributions measured by the EBT and RTQA radiochromic film. In both cases, the measured dose distributions were compared to the dose distributions calculated by the treatment planning system (TPS). We also compared dose distributions using three different conformity indices at a 95% isodose.

Results

Better target coverage and better compliance of measurements (semiconductor detectors and radiochromic films) with calculated doses was obtained for cylindrical target than for cuboidal target. The 95% isodose covered well the tumor for both target shapes, while for cuboidal target larger volume around the target received therapeutic dose, due to the complicated target shape. The use wax boluses provided to be effective tool in modifying proton beam to achieve appropriate shape of isodose distribution.

Conclusion

EBT film yielded the best visual matching. Both EBT and RTQA films confirmed good conformity between calculated and measured doses, thus confirming that wax boluses used to modify the proton beam resulted in good dose distributions.     

A Polymeric Prodrug of 5-Fluorouracil-1-Acetic Acid Using a Multi-Hydroxyl Polyethylene Glycol Derivative as the Drug Carrier

Purpose

Macromolecular prodrugs obtained by covalently conjugating small molecular drugs with polymeric carriers were proven to accomplish controlled and sustained release of the therapeutic agents in vitro and in vivo. Polyethylene glycol (PEG) has been extensively used due to its low toxicity, low immunogenicity and high biocompatibility. However, for linear PEG macromolecules, the number of available hydroxyl groups for drug coupling does not change with the length of polymeric chain, which limits the application of PEG for drug conjugation purposes. To increase the drug loading and prolong the retention time of 5-fluorouracil (5-Fu), a macromolecular prodrug of 5-Fu, 5-fluorouracil-1 acid-PAE derivative (5-FA-PAE) was synthesized and tested for the antitumor activity in vivo.

Methods

PEG with a molecular weight of 38 kDa was selected to synthesize the multi-hydroxyl polyethylene glycol derivative (PAE) through an addition reaction. 5-fluorouracil-1 acetic acid (5-FA), a 5-Fu derivative was coupled with PEG derivatives via ester bond to form a macromolecular prodrug, 5-FA-PAE. The in vitro drug release, pharmacokinetics, in vivo distribution and antitumor effect of the prodrug were investigated, respectively.

Results

The PEG-based prodrug obtained in this study possessed an exceedingly high 5-FA loading efficiency of 10.58%, much higher than the maximum drug loading efficiency of unmodified PEG with the same molecular weight, which was 0.98% theoretically. Furthermore, 5-FA-PAE exhibited suitable sustained release in tumors.

Conclusion

This study provides a new approach for the development of the delivery to tumors of anticancer agents with PEG derivatives.     

Availability of and Ease of Access to Calorie Information on Restaurant Websites

Objective

Offering calories on restaurant websites might be particularly important for consumer meal planning, but the availability of and ease of accessing this information are unknown.

Methods

We assessed websites for the top 100 U.S. chain restaurants to determine the availability of and ease of access to calorie information as well as website design characteristics. We also examined potential predictors of calorie availability and ease of access.

Results

Eighty-two percent of restaurants provided calorie information on their websites; 25% presented calories on a mobile-formatted website. On average, calories could be accessed in 2.35±0.99 clicks. About half of sites (51.2%) linked to calorie information via the homepage. Fewer than half had a separate section identifying healthful options (46.3%), or utilized interactive meal planning tools (35.4%). Quick service/fast casual, larger restaurants, and those with less expensive entrées and lower revenue were more likely to make calorie information available. There were no predictors of ease of access.

Conclusion

Calorie information is both available and largely accessible on the websites of America’s leading restaurants. It is unclear whether consumer behavior is affected by the variability in the presentation of calorie information.     

Mistletoes and mutant albino shoots on woody plants as mineral nutrient traps

Background and Aims

Potassium, sulphur and zinc contents of mistletoe leaves are generally higher than in their hosts. This is attributed to the fact that chemical elements which are cycled between xylem and phloem in the process of phloem loading of sugars are trapped in the mistletoe, because these parasites do not feed their hosts. Here it is hypothesized that mutant albino shoots on otherwise green plants should behave similarly, because they lack photosynthesis and thus cannot recycle elements involved in sugar loading.

Methods

The mineral nutrition of the mistletoe Scurrula elata was compared with that of albino shoots on Citrus sinensis and Nerium oleander. The potential for selective nutrient uptake by the mistletoe was studied by comparing element contents of host leaves on infected and uninfected branches and by manipulation of the haustorium–shoot ratio in mistletoes. Phloem anatomy of albino leaves was compared with that of green leaves.

Key Results

Both mistletoes and albino leaves had higher contents of potassium, sulphur and zinc than hosts or green leaves, respectively. Hypothetical discrimination of nutrient elements during the uptake by the haustorium is not supported by our data. Anatomical studies of albino leaves showed characteristics of release phloem.

Conclusions

Both albino shoots and mistletoes are traps for elements normally recycled between xylem and phloem, because retranslocation of phloem mobile elements into the mother plant or the host is low or absent. It can be assumed that the lack of photosynthetic activity in albino shoots and thus of sugars needed in phloem loading is responsible for the accumulation of elements. The absence of phloem loading is reflected in phloem anatomy of these abnormal shoots. In mistletoes the evolution of a parasitic lifestyle has obviously eliminated substantial feeding of the host with photosynthates produced by the mistletoe.     

Two-dimensional imaging of tumour control probabilities and normal tissue complication probabilities

Aim

To create a presentation method of TCP and NTCP distributions calculated based on dose distribution for a selected CT slice.

Materials and methods

Three 24-bit colour maps – of dose distribution, delineated structures and CT information – were converted into m-by-n-by-3 data arrays, containing intensities of red, green, and blue colour components for each pixel. All calculations were performed with Matlab v.6.5. The transformation function, which consists of five linear functions, was prepared to translate the colour map into a one-dimensional data array of dose values. A menu-driven application based on the transformation function and mathematical models of complication risk (NTCP) and treatment control probability (TCP) was designed to allow pixel-by-pixel translation of colour maps into one-dimensional arrays of TCP and NTCP values.

Results

The result of this work is an application created to visualize the TCP and NTCP distribution for a single CT scan based on the spatial dose distribution calculated in the treatment planning system. The application allows 10 targets (PTV) and 10 organs at risks (OaR) to be defined. The interface allows alpha/beta values to be inserted for each delineated structure. The application computes TCP and NTCP matrices, which are presented as colour maps superimposed on the corresponding CT slice. There is a set of parameters used for TCP/NTCP calculations which can be defined by the user.

Conclusion

Our application is a prototype of an evaluation tool. Although limited to a single plane of the treatment plan, it is believed to be a starting point for further development.