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Constitutive laws that describe the mechanical responses of cardiac tissue under loading hold the key to accurately model the biomechanical behaviour of the heart. There have been ample choices of phenomenological constitutive laws derived from experiments, some of which are quite sophisticated and include effects of microscopic fibre structures of the myocardium. A typical example is the strain-invariant-based Holzapfel–Ogden 2009 model that is excellently fitted to simple shear tests. It has been widely used and regarded as the state-of-the-art constitutive law for myocardium. However, there has been no analysis to show if it has both adequate descriptive and predictive capabilities for other tissue tests of myocardium. Indeed, such an analysis is important for any constitutive laws for clinically useful computational simulations. In this work, we perform such an analysis using combinations of tissue tests, uniaxial tension, biaxial tension and simple shear from three different sets of myocardial tissue studies. Starting from the general 14-parameter myocardial constitutive law developed by Holzapfel and Ogden, denoted as the general HO model, we show that this model has good descriptive and predictive capabilities for all the experimental tests. However, to reliably determine all 14 parameters of the model from experiments remains a great challenge. Our aim is to reduce the constitutive law using Akaike information criterion, to maintain its mechanical integrity whilst achieving minimal computational cost. A competent constitutive law should have descriptive and predictive capabilities for different tissue tests. By competent, we mean the model has least terms but is still able to describe and predict experimental data. We also investigate the optimal combinations of tissue tests for a given constitutive model. For example, our results show that using one of the reduced HO models, one may need just one shear response (along normal-fibre direction) and one biaxial stretch (ratio of 1 mean fibre : 1 cross-fibre) to satisfactorily describe Sommer et al. human myocardial mechanical properties. Our study suggests that single-state tests (i.e. simple shear or stretching only) are insufficient to determine the myocardium responses. We also found it is important to consider transmural fibre rotations within each myocardial sample of tests during the fitting process. This is done by excluding un-stretched fibres using an “effective fibre ratio”, which depends on the sample size, shape, local myofibre architecture and loading conditions. We conclude that a competent myocardium material model can be obtained from the general HO model using AIC analysis and a suitable combination of tissue tests.

The development of methods for dealing with continuous data with a spike at zero has lagged behind those for overdispersed or zero‐inflated count data. We consider longitudinal ecological data corresponding to an annual average of 26 weekly maximum counts of birds, and are hence effectively continuous, bounded below by zero but also with a discrete mass at zero. We develop a Bayesian hierarchical Tweedie regression model that can directly accommodate the excess number of zeros common to this type of data, whilst accounting for both spatial and temporal correlation. Implementation of the model is conducted in a Markov chain Monte Carlo (MCMC) framework, using reversible jump MCMC to explore uncertainty across both parameter and model spaces. This regression modelling framework is very flexible and removes the need to make strong assumptions about mean‐variance relationships a priori. It can also directly account for the spike at zero, whilst being easily applicable to other types of data and other model formulations. Whilst a correlative study such as this cannot prove causation, our results suggest that an increase in an avian predator may have led to an overall decrease in the number of one of its prey species visiting garden feeding stations in the United Kingdom. This may reflect a change in behaviour of house sparrows to avoid feeding stations frequented by sparrowhawks, or a reduction in house sparrow population size as a result of sparrowhawk increase. Publisher PDF

Motivation Data processing is a key bottleneck for 1H NMR-based metabolic profiling of complex biological mixtures, such as biofluids. These spectra typically contain several thousands of signals, corresponding to possibly few hundreds of metabolites. A number of binning-based methods have been proposed to reduce the dimensionality of 1 D 1H NMR datasets, including statistical recoupling of variables (SRV). Here, we introduce a new binning method, named JBA (“pJRES Binning Algorithm”), which aims to extend the applicability of SRV to pJRES spectra. Results The performance of JBA is comprehensively evaluated using 617 plasma 1H NMR spectra from the FGENTCARD cohort. The results presented here show that JBA exhibits higher sensitivity than SRV to detect peaks from low-abundance metabolites. In addition, JBA allows a more efficient removal of spectral variables corresponding to pure electronic noise, and this has a positive impact on multivariate model building Availability and implementation The algorithm is implemented using the MWASTools R/Bioconductor package. Supplementary information Supplementary data are available at Bioinformatics online.

In the organosolv pulping of the oil palm fronds, the influence of the operational variables of the pulping reactor (viz. cooking temperature and time, ethanol and NaOH concentration) on the properties of the resulting pulp (yield and kappa number) and paper sheets (tensile index and tear index) was investigated using a wavelet neural network model. The experimental results with error less than 0.0965 (in terms of MSE) were produced, and were then compared with those obtained from the response surface methodology. Performance assessment indicated that the neural network model possessed superior predictive ability than the polynomial model, since a very close agreement between the experimental and the predicted values was obtained.

Motivation: Modern protein sequencing techniques have led to the determination of >50 million protein sequences. ProtoNet is a clustering system that provides a continuous hierarchical agglomerative clustering tree for all proteins. While ProtoNet performs unsupervised classification of all included proteins, finding an optimal level of granularity for the purpose of focusing on protein functional groups remain elusive. Here, we ask whether knowledge-based annotations on protein families can support the automatic unsupervised methods for identifying high-quality protein families. We present a method that yields within the ProtoNet hierarchy an optimal partition of clusters, relative to manual annotation schemes. The method’s principle is to minimize the entropy-derived distance between annotation-based partitions and all available hierarchical partitions. We describe the best front (BF) partition of 2 478 328 proteins from UniRef50. Of 4 929 553 ProtoNet tree clusters, BF based on Pfam annotations contain 26 891 clusters. The high quality of the partition is validated by the close correspondence with the set of clusters that best describe thousands of keywords of Pfam. The BF is shown to be superior to naïve cut in the ProtoNet tree that yields a similar number of clusters. Finally, we used parameters intrinsic to the clustering process to enrich a priori the BF’s clusters. We present the entropy-based method’s benefit in overcoming the unavoidable limitations of nested clusters in ProtoNet. We suggest that this automatic information-based cluster selection can be useful for other large-scale annotation schemes, as well as for systematically testing and comparing putative families derived from alternative clustering methods. Availability and implementation: A catalog of BF clusters for thousands of Pfam keywords is provided at http://protonet.cs.huji.ac.il/bestFront/ Contact: michall@cc.huji.ac.il

Motivation: Somatic copy number aberrations (SCNAs) are frequent in cancer genomes, but many of these are random, passenger events. A common strategy to distinguish functional aberrations from passengers is to identify those aberrations that are recurrent across multiple samples. However, the extensive variability in the length and position of SCNAs makes the problem of identifying recurrent aberrations notoriously difficult. Results: We introduce a combinatorial approach to the problem of identifying independent and recurrent SCNAs, focusing on the key challenging of separating the overlaps in aberrations across individuals into independent events. We derive independent and recurrent SCNAs as maximal cliques in an interval graph constructed from overlaps between aberrations. We efficiently enumerate all such cliques, and derive a dynamic programming algorithm to find an optimal selection of non-overlapping cliques, resulting in a very fast algorithm, which we call RAIG (Recurrent Aberrations from Interval Graphs). We show that RAIG outperforms other methods on simulated data and also performs well on data from three cancer types from The Cancer Genome Atlas (TCGA). In contrast to existing approaches that employ various heuristics to select independent aberrations, RAIG optimizes a well-defined objective function. We show that this allows RAIG to identify rare aberrations that are likely functional, but are obscured by overlaps with larger passenger aberrations. Availability: http://compbio.cs.brown.edu/software. Contact: braphael@brown.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Article, Motivation A dominant approach to genetic association studies is to perform univariate tests between genotype-phenotype pairs. However, analyzing related traits together increases statistical power, and certain complex associations become detectable only when several variants are tested jointly. Currently, modest sample sizes of individual cohorts, and restricted availability of individual-level genotype-phenotype data across the cohorts limit conducting multivariate tests. Results We introduce metaCCA , a computational framework for summary statistics-based analysis of a single or multiple studies that allows multivariate representation of both genotype and phenotype. It extends the statistical technique of canonical correlation analysis to the setting where original individual-level records are not available, and employs a covariance shrinkage algorithm to achieve robustness. Multivariate meta-analysis of two Finnish studies of nuclear magnetic resonance metabolomics by metaCCA , using standard univariate output from the program SNPTEST, shows an excellent agreement with the pooled individual-level analysis of original data. Motivated by strong multivariate signals in the lipid genes tested, we envision that multivariate association testing using metaCCA has a great potential to provide novel insights from already published summary statistics from high-throughput phenotyping technologies., published version, peerReviewed

QSAR/QSPR (quantitative structure‐activity/property relationship) modeling has been a prevalent approach in various, overlapping sub‐fields of computational, medicinal and environmental chemistry for decades. The generation and selection of molecular descriptors is an essential part of this process. In typical QSAR workflows, the starting pool of molecular descriptors is rationalized based on filtering out descriptors which are (i) constant throughout the whole dataset, or (ii) very strongly correlated to another descriptor. While the former is fairly straightforward, the latter involves a level of subjectivity when deciding what exactly is considered to be a strong correlation. Despite that, most QSAR modeling studies do not report on this step. In this study, we examine in detail the effect of various possible descriptor intercorrelation limits on the resulting QSAR models. Statistical comparisons are carried out based on four case studies from contemporary QSAR literature, using a combined methodology based on sum of ranking differences (SRD) and analysis of variance (ANOVA).

Motivation: Recent attempts to account for multiple testing in the analysis of microarray data have focused on controlling the false discovery rate (FDR), which is defined as the expected percentage of the number of false positive genes among the claimed significant genes. As a consequence, the accuracy of the FDR estimators will be important for correctly controlling FDR. Xie et al. found that the standard permutation method of estimating FDR is biased and proposed to delete the predicted differentially expressed (DE) genes in the estimation of FDR for one-sample comparison. However, we notice that the formula of the FDR used in their paper is incorrect. This makes the comparison results reported in their paper unconvincing. Other problems with their method include the biased estimation of FDR caused by over- or under-deletion of DE genes in the estimation of FDR and by the implicit use of an unreasonable estimator of the true proportion of equivalently expressed (EE) genes. Due to the great importance of accurate FDR estimation in microarray data analysis, it is necessary to point out such problems and propose improved methods. Results: Our results confirm that the standard permutation method overestimates the FDR. With the correct FDR formula, we show the method of Xie et al. always gives biased estimation of FDR: it overestimates when the number of claimed significant genes is small, and underestimates when the number of claimed significant genes is large. To overcome these problems, we propose two modifications. The simulation results show that our estimator gives more accurate estimation. Contact: szhang3@unl.edu

We propose a nonscanning three-dimensional (3-D) fluorescence imaging technique using the transport of intensity equation (TIE) and free-space Fresnel propagation. In this imaging technique, a phase distribution corresponding to defocused fluorescence images with a point-light-source-like shape is retrieved by a TIE-based phase retrieval algorithm. From the obtained phase distribution, and its corresponding amplitude distribution, of the defocused fluorescence image, various images at different distances can be reconstructed at the desired plane after Fresnel propagation of the complex wave function. Through the proposed imaging approach, the 3-D fluorescence imaging can be performed in multiple planes. The fluorescence intensity images are captured with the help of an electrically tunable lens; hence, the imaging technique is free from motion artifacts. We present experimental results corresponding to microbeads and a biological sample to demonstrate the proposed 3-D fluorescence imaging technique.

A new canopy photosynthesis model and its related parameterization protocol are presented. The model can be used to dissect factors controlling canopy radiation use efficiency and in rice ideotype design., In current rice breeding programs, morphological parameters such as plant height, leaf length and width, leaf angle, panicle architecture, and tiller number during the grain filling stage are used as major selection targets. However, so far, there is no robust approach to quantitatively define the optimal combinations of parameters that can lead to increased canopy radiation use efficiency (RUE). Here we report the development of a three-dimensional canopy photosynthesis model (3dCAP), which effectively combines three-dimensional canopy architecture, canopy vertical nitrogen distribution, a ray-tracing algorithm, and a leaf photosynthesis model. Concurrently, we developed an efficient workflow for the parameterization of 3dCAP. 3dCAP predicted daily canopy RUE for different nitrogen treatments of a given rice cultivar under different weather conditions. Using 3dCAP, we explored the influence of three canopy architectural parameters—tiller number, tiller angle and leaf angle—on canopy RUE. Under different weather conditions and different nitrogen treatments, canopy architecture optimized by manipulating these parameters can increase daily net canopy photosynthetic CO2 uptake by 10–52%. Generally, a smaller tiller angle was predicted for most elite rice canopy architectures, especially under scattered light conditions. Results further show that similar canopy RUE can be obtained by multiple different parameter combinations; these combinations share two common features of high light absorption by leaves in the canopy and a high level of coordination between the nitrogen concentration and the light absorbed by each leaf within the canopy. Overall, this new model has potential to be used in rice ideotype design for improved canopy RUE.

Paralumbar muscle performance and fatigue were evaluated by measuring electromagnetic activity during entire body vibration (EBV) in 44 healthy subjects. Physical fitness of subjects was estimated on a 5-degree scale. Electric activity was recorded in 200 seconds with 1 kHz sampling on the Biopac Student Lab during EBV. Data were used to produce time series for two vectors of the phase space and spatial axis: X (left-right), Y (up-down) and Z (ventral-dorsal). Time series were evaluated by calculating fractal dimension by the R/S algorithm. Movement of the electric field along the Y-axis showed changes (up-down) extracted in the first and second quarter of the measurement (p=0.02 and p=0.03, respectively). These changes were not specific for gender but showed dependence on subject age and fitness. The fractal dimension values by the R/S algorithm were larger in female subjects. Results suggested the electric field changes during EBV in the up-down direction to contain information on muscular performance and fatigue, not dependent on gender, but on the age and degree of overall physical fitness., Istraživanje električnog polja paralumbalne muskulature kao pokazatelja umaranja provedeno je na 44 zdrava ispitanika, pri čemu je utreniranost njihove paralumbalne muskulature procijenjena anamnestički ljestvicom od 5 stupnjeva. Električna aktivnost snimana je uređajem Biopac Student Lab i uporabom tri para elektroda postavljenih duž osi faznog prostora. Iz prikupljenih podataka izostavljeni su dijelovi koji odgovaraju QRS kompleksu EKG-a i rekonstruirani sljedovi pet različitih načina mjerenja električne aktivnosti, pri čemu su za prva tri izdvojeni zapisi za svaku os. Za os X lijevo i desno, za os Y gore i dolje te za os Z naprijed i nazad, a izračunata su i dva vektora. Iz tako dobivenih vremenskih serija računala se fraktalna dimenzija R/S algoritmom. Od rezultata izračunom fraktal-ne dimenzije zapisa R/S algoritmom izdvaja se kretanje električnog polja duž osi Y (gore-dolje) u prvoj i drugoj četvrtini mjerenja (p=0,02 odnosno p=0,03). Rezultati su se pokazali neovisnima o spolu, ali ovisnima o godinama i utreniranosti ispitanika. Vrijednosti fraktalne dimenzije po R/S algoritmu u žena su bile veće. Navedeno upućuje na to da podaci o kretanju položaja mjerenja duž osi Y (gore-dolje) u sebi sadrže informacije o načinu umaranja muskulature koje nisu ovisne o spolu, nego o dobi i stupnju utreniranosti.

Objective:Uncertainties in radiotherapy target structures are partly dependent on differences between volume calculation and margin growing methods in treatment planning systems (TPS). These uncertainties are exacerbated with very small structures such as those common in stereotactic radiosurgery.Methods:Data from a national commissioning programme for SRS was used to assess variation in reported volumes for six benchmark cases, including malignant and benign indications. Reported volumes were compared both with and without any margins added according to local practice.Results:137 plans were submitted, with a total of 311 structures and covering seven TPS. For volumes 1 cm3 agreement was within 5%. Systematic differences were seen between TPS, partly because of different methods for calculating the end slice volume. About one third of structures had a margin added, of 1–2 mm. Most TPS over-grew the volumes, compared to the approximation of a perfect...

Motivation: Protein domains are subunits that can fold and evolve independently. Identification of domain boundary locations is often the first step in protein folding and function annotations. Most of the current methods deduce domain boundaries by sequence-based analysis, which has low accuracy. There is no efficient method for predicting discontinuous domains that consist of segments from separated sequence regions. As template-based methods are most efficient for protein 3D structure modeling, combining multiple threading alignment information should increase the accuracy and reliability of computational domain predictions. Result: We developed a new protein domain predictor, ThreaDom, which deduces domain boundary locations based on multiple threading alignments. The core of the method development is the derivation of a domain conservation score that combines information from template domain structures and terminal and internal alignment gaps. Tested on 630 non-redundant sequences, without using homologous templates, ThreaDom generates correct single- and multi-domain classifications in 81% of cases, where 78% have the domain linker assigned within ±20 residues. In a second test on 486 proteins with discontinuous domains, ThreaDom achieves an average precision 84% and recall 65% in domain boundary prediction. Finally, ThreaDom was examined on 56 targets from CASP8 and had a domain overlap rate 73, 87 and 85% with the target for Free Modeling, Hard multiple-domain and discontinuous domain proteins, respectively, which are significantly higher than most domain predictors in the CASP8. Similar results were achieved on the targets from the most recently CASP9 and CASP10 experiments. Availability: http://zhanglab.ccmb.med.umich.edu/ThreaDom/. Contact: ude.hcimu@gnhz Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation: Similarity search is the foundation of bioinformatics. It plays a key role in establishing structural, functional and evolutionary relationships between biological sequences. Although the power of the similarity search has increased steadily in recent years, a high percentage of sequences remain uncharacterized in the protein universe. Thus, new similarity search strategies are needed to efficiently and reliably infer the structure and function of new sequences. The existing paradigm for studying protein sequence, structure, function and evolution has been established based on the assumption that the protein universe is discrete and hierarchical. Cumulative evidence suggests that the protein universe is continuous. As a result, conventional sequence homology search methods may be not able to detect novel structural, functional and evolutionary relationships between proteins from weak and noisy sequence signals. To overcome the limitations in existing similarity search methods, we propose a new algorithmic framework—Enrichment of Network Topological Similarity (ENTS)—to improve the performance of large scale similarity searches in bioinformatics. Results: We apply ENTS to a challenging unsolved problem: protein fold recognition. Our rigorous benchmark studies demonstrate that ENTS considerably outperforms state-of-the-art methods. As the concept of ENTS can be applied to any similarity metric, it may provide a general framework for similarity search on any set of biological entities, given their representation as a network. Availability and implementation: Source code freely available upon request Contact: lxie@iscb.org

Motivation: Sequence homology searches are used in various fields. New sequencing technologies produce huge amounts of sequence data, which continuously increase the size of sequence databases. As a result, homology searches require large amounts of computational time, especially for metagenomic analysis. Results: We developed a fast homology search method based on database subsequence clustering, and implemented it as GHOSTZ. This method clusters similar subsequences from a database to perform an efficient seed search and ungapped extension by reducing alignment candidates based on triangle inequality. The database subsequence clustering technique achieved an ∼2-fold increase in speed without a large decrease in search sensitivity. When we measured with metagenomic data, GHOSTZ is ∼2.2–2.8 times faster than RAPSearch and is ∼185–261 times faster than BLASTX. Availability and implementation: The source code is freely available for download at http://www.bi.cs.titech.ac.jp/ghostz/ Contact: akiyama@cs.titech.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online.

Knowledge regarding the 3D structure of a protein provides useful information about the protein’s functional properties. Particularly, structural similarity between proteins can be used as a good predictor of functional similarity. One method that uses the 3D geometrical structure of proteins in order to compare them is the similarity value (SV). In this paper, we introduce a new definition of the SV measure for comparing two proteins. To this end, we consider the mass of the protein’s atoms and concentrate on the number of protein’s atoms to be compared. This defines a new measure, called the weighted similarity value (WSV), adding physical properties to geometrical properties. We also show that our results are in good agreement with the results obtained by TM-SCORE and DALILITE. WSV can be of use in protein classification and in drug discovery.

Motivation: We propose a novel algorithm to combine multiple kernels and Laplacians for clustering analysis. The new algorithm is formulated on a Rayleigh quotient objective function and is solved as a bi-level alternating minimization procedure. Using the proposed algorithm, the coefficients of kernels and Laplacians can be optimized automatically. Results: Three variants of the algorithm are proposed. The performance is systematically validated on two real-life data fusion applications. The proposed Optimized Kernel Laplacian Clustering (OKLC) algorithms perform significantly better than other methods. Moreover, the coefficients of kernels and Laplacians optimized by OKLC show some correlation with the rank of performance of individual data source. Though in our evaluation the K values are predefined, in practical studies, the optimal cluster number can be consistently estimated from the eigenspectrum of the combined kernel Laplacian matrix. Availability: The MATLAB code of algorithms implemented in this paper is downloadable from http://homes.esat.kuleuven.be/~sistawww/bioi/syu/oklc.html. Contact: shiyu@uchicago.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Motivation Protein solubility can be a decisive factor in both research and production efficiency, and in silico sequence-based predictors that can accurately estimate solubility outcomes are highly sought. Results In this study, we present a novel approach termed PRotein SolubIlity Predictor (PaRSnIP), which uses a gradient boosting machine algorithm as well as an approximation of sequence and structural features of the protein of interest. Based on an independent test set, PaRSnIP outperformed other state-of-the-art sequence-based methods by more than 9% in accuracy and 0.17 in Matthew’s correlation coefficient, with an overall accuracy of 74% and Matthew’s correlation coefficient of 0.48. Additionally, PaRSnIP provides importance scores for all features used in training. We observed higher fractions of exposed residues to associate positively with protein solubility and tripeptide stretches with multiple histidines to associate negatively with solubility. The improved prediction accuracy of PaRSnIP should enable it to predict protein solubility with greater reliability and to screen for sequence variants with enhanced manufacturability. Availability and implementation PaRSnIP software is available for download under GitHub (https://github.com/RedaRawi/PaRSnIP). Supplementary information Supplementary data are available at Bioinformatics online.

Motivation Studies, mostly from the operations/management literature, have shown that the rate of human error increases with task complexity. What is not known is how many errors make it into the published literature, given that they must slip by peer-review. By identifying paired, dependent values within text for reported calculations of varying complexity, we can identify discrepancies, quantify error rates and identify mitigating factors. Results We extracted statistical ratios from MEDLINE abstracts (hazard ratio, odds ratio, relative risk), their 95% CIs, and their P-values. We re-calculated the ratios and P-values using the reported CIs. For comparison, we also extracted percent–ratio pairs, one of the simplest calculation tasks. Over 486 000 published values were found and analyzed for discrepancies, allowing for rounding and significant figures. Per reported item, discrepancies were less frequent in percent–ratio calculations (2.7%) than in ratio–CI and P-value calculations (5.6–7.5%), and smaller discrepancies were more frequent than large ones. Systematic discrepancies (multiple incorrect calculations of the same type) were higher for more complex tasks (14.3%) than simple ones (6.7%). Discrepancy rates decreased with increasing journal impact factor (JIF) and increasing number of authors, but with diminishing returns and JIF accounting for most of the effect. Approximately 87% of the 81 937 extracted P-values were ≤ 0.05. Conclusion Using a simple, yet accurate, approach to identifying paired values within text, we offer the first quantitative evaluation of published error frequencies within these types of calculations. Supplementary information Supplementary data are available at Bioinformatics online.

A micro-finite element-based method to estimate the bone loading history based on bone architecture was recently presented in the literature. However, a thorough investigation of the parameter sensitivity and plausibility of this method to predict joint loads is still missing. The goals of this study were (1) to analyse the parameter sensitivity of the joint load predictions at one proximal femur and (2) to assess the plausibility of the results by comparing load predictions of ten proximal femora to in vivo hip joint forces measured with instrumented prostheses (available from www.orthoload.com). Joint loads were predicted by optimally scaling the magnitude of four unit loads (inclined \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$-20^{\circ }$$\end{document}-20∘ to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$100^{\circ }$$\end{document}100∘ with respect to the vertical axis) applied to micro-finite element models created from high-resolution computed tomography scans (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$30.3~\upmu $$\end{document}30.3μm voxel size). Parameter sensitivity analysis was performed by varying a total of nine parameters and showed that predictions of the peak load directions (range 10\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{\circ }$$\end{document}∘–\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$30^{\circ }$$\end{document}30∘) are more robust than the predicted peak load magnitudes (range 2344.8–4689.5 N). Comparing the results of all ten femora with the in vivo loading data of ten subjects showed that peak loads are plausible both in terms of the load direction (in vivo: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$18.2\pm 2.0^{\circ }$$\end{document}18.2±2.0∘, predicted: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$20.0^{\circ }$$\end{document}20.0∘) and magnitude (in vivo: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$2707.6\pm 443.3~\hbox {N}$$\end{document}2707.6±443.3N, predicted: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$3372.2\pm 597.9~\hbox {N}$$\end{document}3372.2±597.9N). Overall, this study suggests that micro-finite element-based joint load predictions are both plausible and robust in terms of the predicted peak load direction, but predicted load magnitudes should be interpreted with caution.

Motivation Apart from meta-predictors, most of today's methods for residue–residue contact prediction are based entirely on Direct Coupling Analysis (DCA) of correlated mutations in multiple sequence alignments (MSAs). These methods are on average ∼40% correct for the 100 strongest predicted contacts in each protein. The end-user who works on a single protein of interest will not know if predictions are either much more or much less correct than 40%, which is especially a problem if contacts are predicted to steer experimental research on that protein. Results We designed a regression model that forecasts the accuracy of residue–residue contact prediction for individual proteins with an average error of 7 percentage points. Contacts were predicted with two DCA methods (gplmDCA and PSICOV). The models were built on parameters that describe the MSA, the predicted secondary structure, the predicted solvent accessibility and the contact prediction scores for the target protein. Results show that our models can be also applied to the meta-methods, which was tested on RaptorX. Availability and implementation All data and scripts are available from http://comprec-lin.iiar.pwr.edu.pl/dcaQ/. Supplementary information Supplementary data are available at Bioinformatics online.

Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizing the expected uncertainty in the effect response of the typical individual. 50 iterations of the MBAODs were run using the MBAOD R-package, with the concentration from a one-compartment first-order absorption pharmacokinetic model driving the population effect response in a sigmoidal EMAX pharmacodynamics model. The initial cohort consisted of eight individuals in two groups and each additional cohort added two individuals receiving a dose optimized as a discrete covariate. The MBAOD designs using lnD and ELD optimality with misspecified initial model parameters were compared by evaluating the efficiency relative to an lnD-optimal design based on the true parameter values. For the explored example model, the MBAOD using ELD-optimal designs converged quicker to the theoretically optimal lnD-optimal design based on the true parameters for both sampling schedules. Thus, using a robust optimality criterion in MBAODs could reduce the number of adaptations required and improve the practicality of adaptive trials using optimal design.

© 2016. Published by Oxford University Press. With expanded access to, and decreased costs of, mass spectrometry, investigators are collecting and analyzing multiple biological matrices from the same subject such as serum, plasma, tissue and urine to enhance biomarker discoveries, understanding of disease processes and identification of therapeutic targets. Commonly, each biological matrix is analyzed separately, but multivariate methods such as MANOVAs that combine information from multiple biological matrices are potentially more powerful. However, mass spectrometric data typically contain large amounts of missing values, and imputation is often used to create complete data sets for analysis. The effects of imputation on multiple biological matrix analyses have not been studied. We investigated the effects of seven imputation methods (half minimum substitution, mean substitution, k-nearest neighbors, local least squares regression, Bayesian principal components analysis, singular value decomposition and random forest), on the within-subject correlation of compounds between biological matrices and its consequences on MANOVA results. Through analysis of three real omics data sets and simulation studies, we found the amount of missing data and imputation method to substantially change the between-matrix correlation structure. The magnitude of the correlations was generally reduced in imputed data sets, and this effect increased with the amount of missing data. Significant results from MANOVA testing also were substantially affected. In particular, the number of false positives increased with the level of missing data for all imputation methods. No one imputation method was universally the best, but the simple substitution methods (Half Minimum and Mean) consistently performed poorly.

The subgroup structure of the hyperoctahedral group in six dimensions is studied, with particular attention to the subgroups isomorphic to the icosahedral group. The orthogonal crystallographic representations of the icosahedral group are classified, and their intersections are studied in some detail, using a combinatorial approach which involves results from graph theory and their spectra., The subgroup structure of the hyperoctahedral group in six dimensions is investigated. In particular, the subgroups isomorphic to the icosahedral group are studied. The orthogonal crystallographic representations of the icosahedral group are classified and their intersections and subgroups analysed, using results from graph theory and their spectra.

Motivation The identification of heterogeneities in cell populations by utilizing single-cell technologies such as single-cell RNA-Seq, enables inference of cellular development and lineage trees. Several methods have been proposed for such inference from high-dimensional single-cell data. They typically assign each cell to a branch in a differentiation trajectory. However, they commonly assume specific geometries such as tree-like developmental hierarchies and lack statistically sound methods to decide on the number of branching events. Results We present K-Branches, a solution to the above problem by locally fitting half-lines to single-cell data, introducing a clustering algorithm similar to K-Means. These halflines are proxies for branches in the differentiation trajectory of cells. We propose a modified version of the GAP statistic for model selection, in order to decide on the number of lines that best describe the data locally. In this manner, we identify the location and number of subgroups of cells that are associated with branching events and full differentiation, respectively. We evaluate the performance of our method on single-cell RNA-Seq data describing the differentiation of myeloid progenitors during hematopoiesis, single-cell qPCR data of mouse blastocyst development, single-cell qPCR data of human myeloid monocytic leukemia and artificial data. Availability and implementation An R implementation of K-Branches is freely available at https://github.com/theislab/kbranches. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation Protein domain prediction is one of the most powerful approaches for sequence-based function prediction. Although domain instances are typically predicted independently of each other, newer approaches have demonstrated improved performance by rewarding domain pairs that frequently co-occur within sequences. However, most of these approaches have ignored the order in which domains preferentially co-occur and have also not modeled domain co-occurrence probabilistically. Results We introduce a probabilistic approach for domain prediction that models ‘directional’ domain context. Our method is the first to score all domain pairs within a sequence while taking their order into account, even for non-sequential domains. We show that our approach extends a previous Markov model-based approach to additionally score all pairwise terms, and that it can be interpreted within the context of Markov random fields. We formulate our underlying combinatorial optimization problem as an integer linear program, and demonstrate that it can be solved quickly in practice. Finally, we perform extensive evaluation of domain context methods and demonstrate that incorporating context increases the number of domain predictions by ∼15%, with our approach dPUC2 (Domain Prediction Using Context) outperforming all competing approaches. Availability and Implementation dPUC2 is available at http://github.com/alexviiia/dpuc2. Supplementary information Supplementary data are available at Bioinformatics online.

In pulmonary hypertension (PH) diagnosis and management, many useful functional markers have been proposed that are unfeasible for clinical implementation. For example, assessing right ventricular (RV) contractile response to a gradual increase in pulmonary arterial (PA) impedance requires simultaneously recording RV pressure and volume, and under different afterload/preload conditions. In addition to clinical applications, many research projects are hampered by limited retrospective clinical data and could greatly benefit from simulations that extrapolate unavailable hemodynamics. The objective of this study was to develop and validate a 0D computational model, along with a numerical implementation protocol, of the RV–PA axis. Model results are qualitatively compared with published clinical data and quantitatively validated against right heart catheterization (RHC) for 115 pediatric PH patients. The RV–PA circuit is represented using a general elastance function for the RV and a three-element Windkessel initial value problem for the PA. The circuit mathematically sits between two reservoirs of constant pressure, which represent the right and left atriums. We compared Pmax, Pmin, mPAP, cardiac output (CO), and stroke volume (SV) between the model and RHC. The model predicted between 96% and 98% of the variability in pressure and 98–99% in volumetric characteristics (CO and SV). However, Bland Altman plots showed the model to have a consistent bias for most pressure and volumetric parameters, and differences between model and RHC to have considerable error. Future studies will address this issue and compare specific waveforms, but these initial results are extremely promising as preliminary proof of concept of the modeling approach.

Stability is essential for designing and controlling any dynamic systems. Recently, the stability of genetic regulatory networks has been widely studied by employing linear matrix inequality (LMI) approach, which results in checking the existence of feasible solutions to high-dimensional LMIs. In the previous study, the authors present several stability conditions for genetic regulatory networks with time-varying delays, based on M -matrix theory and using the non-smooth Lyapunov function, which results in determining whether a low-dimensional matrix is a non-singular M -matrix. However, the previous approach cannot be applied to analyse the stability of genetic regulatory networks with noise perturbations. Here, the authors design a smooth Lyapunov function quadratic in state variables and employ M -matrix theory to derive new stability conditions for genetic regulatory networks with time-varying delays. Theoretically, these conditions are less conservative than existing ones in some genetic regulatory networks. Then the results are extended to genetic regulatory networks with time-varying delays and noise perturbations. For genetic regulatory networks with n genes and n proteins, the derived conditions are to check if an n × n matrix is a non-singular M -matrix. To further present the new theories proposed in this study, three example regulatory networks are analysed.