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Motivation Read alignment is central to many aspects of modern genomics. Most aligners use heuristics to accelerate processing, but these heuristics can fail to find the optimal alignments of reads. Alignment accuracy is typically measured through simulated reads; however, the simulated location may not be the (only) location with the optimal alignment score. Results Vargas implements a heuristic-free algorithm guaranteed to find the highest-scoring alignment for real sequencing reads to a linear or graph genome. With semiglobal and local alignment modes and affine gap and quality-scaled mismatch penalties, it can implement the scoring functions of commonly used aligners to calculate optimal alignments. While this is computationally intensive, Vargas uses multi-core parallelization and vectorized (SIMD) instructions to make it practical to optimally align large numbers of reads, achieving a maximum speed of 456 billion cell updates per second. We demonstrate how these ‘gold standard’ Vargas alignments can be used to improve heuristic alignment accuracy by optimizing command-line parameters in Bowtie 2, BWA-maximal exact match and vg to align more reads correctly. Availability and implementation Source code implemented in C++ and compiled binary releases are available at https://github.com/langmead-lab/vargas under the MIT license. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation Protein domains are subunits that can fold and function independently. Correct domain boundary assignment is thus a critical step toward accurate protein structure and function analyses. There is, however, no efficient algorithm available for accurate domain prediction from sequence. The problem is particularly challenging for proteins with discontinuous domains, which consist of domain segments that are separated along the sequence. Results We developed a new algorithm, FUpred, which predicts protein domain boundaries utilizing contact maps created by deep residual neural networks coupled with coevolutionary precision matrices. The core idea of the algorithm is to retrieve domain boundary locations by maximizing the number of intra-domain contacts, while minimizing the number of inter-domain contacts from the contact maps. FUpred was tested on a large-scale dataset consisting of 2549 proteins and generated correct single- and multi-domain classifications with a Matthew’s correlation coefficient of 0.799, which was 19.1% (or 5.3%) higher than the best machine learning (or threading)-based method. For proteins with discontinuous domains, the domain boundary detection and normalized domain overlapping scores of FUpred were 0.788 and 0.521, respectively, which were 17.3% and 23.8% higher than the best control method. The results demonstrate a new avenue to accurately detect domain composition from sequence alone, especially for discontinuous, multi-domain proteins. Availability and implementation https://zhanglab.ccmb.med.umich.edu/FUpred. Supplementary information Supplementary data are available at Bioinformatics online.

Piwi-interacting RNAs (piRNAs) are indispensable in the transposon silencing, including in germ cell formation, germline stem cell maintenance, spermatogenesis, and oogenesis. piRNA pathways are amongst the major genome defence mechanisms, which maintain genome integrity. They also have important functions in tumorigenesis, as indicated by aberrantly expressed piRNAs being recently shown to play roles in the process of cancer development. A number of computational methods for this have recently been proposed, but they still have not yielded satisfactory predictive performance. Moreover, only one computational method that identifies whether piRNAs function in inducting target mRNA deadenylation been reported in the literature. In this study, we developed a two-layered integrated classifier algorithm, 2lpiRNApred. It identifies piRNAs in the first layer and determines whether they function in inducting target mRNA deadenylation in the second layer. A new feature selection algorithm, which was based on Luca fuzzy entropy and Gaussian membership function (LFE-GM), was proposed to reduce the dimensionality of the features. Five feature extraction strategies, namely, Kmer, General parallel correlation pseudo-dinucleotide composition, General series correlation pseudo-dinucleotide composition, Normalized Moreau-Broto autocorrelation, and Geary autocorrelation, and two types of classifier, Sparse Representation Classifier (SRC) and support vector machine with Mahalanobis distance-based radial basis function (SVMMDRBF), were used to construct a two-layered integrated classifier algorithm, 2lpiRNApred. The results indicate that 2lpiRNApred performs significantly better than six other existing prediction tools.

Motivation Tracking disease outbreaks by whole-genome sequencing leads to the collection of large samples of closely related sequences. Five years ago, we published a method to accurately compute all pairwise distances for such samples by indexing each sequence. Since indexing is slow, we now ask whether it is possible to achieve similar accuracy when indexing only a single sequence. Results We have implemented this idea in the program phylonium and show that it is as accurate as its predecessor and roughly 100 times faster when applied to all 2678 Escherichia coli genomes contained in ENSEMBL. One of the best published programs for rapidly computing pairwise distances, mash, analyzes the same dataset four times faster but, with default settings, it is less accurate than phylonium. Availability and implementation Phylonium runs under the UNIX command line; its C++ sources and documentation are available from github.com/evolbioinf/phylonium. Supplementary information Supplementary data are available at Bioinformatics online.

Accumulating studies have shown that microRNAs (miRNAs) could be used as targets of small-molecule (SM) drugs to treat diseases. In recent years, researchers have proposed many computational models to reveal miRNA-SM associations due to the huge cost of experimental methods. Considering the shortcomings of the previous models, such as the prediction accuracy of some models is low or some cannot be applied for new SMs (miRNAs), we developed a novel model named Symmetric Nonnegative Matrix Factorization for Small Molecule-MiRNA Association prediction (SNMFSMMA). Different from some models directly applying the integrated similarities, SNMFSMMA first performed matrix decomposition on the integrated similarity matrixes, and calculated the Kronecker product of the new integrated similarity matrixes to obtain the SM-miRNA pair similarity. Further, we applied regularized least square to obtain the mapping function of the SM-miRNA pairs to the associated probabilities by minimizing the objective function. On the basis of Dataset 1 and 2 extracted from SM2miR v1.0 database, we implemented global leave-one-out cross validation (LOOCV), miRNA-fixed local LOOCV, SM-fixed local LOOCV and 5-fold cross-validation to evaluate the prediction performance. Finally, the AUC values obtained by SNMFSMMA in these validation reached 0.9711 (0.8895), 0.9698 (0.8884), 0.8329 (0.7651) and 0.9644 ± 0.0035 (0.8814 ± 0.0033) based on Dataset 1 (Dataset 2), respectively. In the first case study, 5 of the top 10 associations predicted were confirmed. In the second, 7 and 8 of the top 10 predicted miRNAs related with 5-FU and 5-Aza-2'-deoxycytidine were confirmed. These results demonstrated the reliable predictive power of SNMFSMMA.

Motivation The increasing availability of annotated genome sequences enables construction of genome-scale metabolic networks, which are useful tools for studying organisms of interest. However, due to incomplete genome annotations, draft metabolic models contain gaps that must be filled in a time-consuming process before they are usable. Optimization-based algorithms that fill these gaps have been developed, however, gap-filling algorithms show significant error rates and often introduce incorrect reactions. Results Here, we present a new gap-filling method that computes the costs of candidate gap-filling reactions from a universal reaction database (MetaCyc) based on taxonomic information. When gap-filling a metabolic model for an organism M (such as Escherichia coli), the cost for reaction R is based on the frequency with which R occurs in other organisms within the phylum of M (in this case, Proteobacteria). The assumption behind this method is that different taxonomic groups are biased toward using different metabolic reactions. Evaluation of the new gap-filler on randomly degraded variants of the EcoCyc metabolic model for E.coli showed an increase in the average F1-score to 99.0 (when using the variable weights by frequency method at the phylum level), compared to 91.0 using the previous MetaFlux gap-filler and 80.3 using a basic gap-filler. Evaluation on two other microbial metabolic models showed similar improvements. Availability and implementation The Pathway Tools software (including MetaFlux) is free for academic use and is available at http://pathwaytools.com. Additional code for reproducing the results presented here is available at www.ai.sri.com/pkarp/pubs/taxgap/supplementary.zip. Supplementary information Supplementary data are available at Bioinformatics online.

Background The COVID-19 pandemic has placed a huge strain on the health care system globally. The metropolitan area of Milan, Italy, was one of the regions most impacted by the COVID-19 pandemic worldwide. Risk prediction models developed by combining administrative databases and basic clinical data are needed to stratify individual patient risk for public health purposes. Objective This study aims to develop a stratification tool aimed at improving COVID-19 patient management and health care organization. Methods A predictive algorithm was developed and applied to 36,834 patients with COVID-19 in Italy between March 8 and the October 9, 2020, in order to foresee their risk of hospitalization. Exposures considered were age, sex, comorbidities, and symptoms associated with COVID-19 (eg, vomiting, cough, fever, diarrhea, myalgia, asthenia, headache, anosmia, ageusia, and dyspnea). The outcome was hospitalizations and emergency department admissions for COVID-19. Discrimination and calibration of the model were also assessed. Results The predictive model showed a good fit for predicting COVID-19 hospitalization (C-index 0.79) and a good overall prediction accuracy (Brier score 0.14). The model was well calibrated (intercept –0.0028, slope 0.9970). Based on these results, 118,804 patients diagnosed with COVID-19 from October 25 to December 11, 2020, were stratified into low, medium, and high risk for COVID-19 severity. Among the overall study population, 67,030 (56.42%) were classified as low-risk patients; 43,886 (36.94%), as medium-risk patients; and 7888 (6.64%), as high-risk patients. In all, 89.37% (106,179/118,804) of the overall study population was being assisted at home, 9% (10,695/118,804) was hospitalized, and 1.62% (1930/118,804) died. Among those assisted at home, most people (63,983/106,179, 60.26%) were classified as low risk, whereas only 3.63% (3858/106,179) were classified at high risk. According to ordinal logistic regression, the odds ratio (OR) of being hospitalized or dead was 5.0 (95% CI 4.6-5.4) among high-risk patients and 2.7 (95% CI 2.6-2.9) among medium-risk patients, as compared to low-risk patients. Conclusions A simple monitoring system, based on primary care data sets linked to COVID-19 testing results, hospital admissions data, and death records may assist in the proper planning and allocation of patients and resources during the ongoing COVID-19 pandemic.

Purpose: To remove the necessity of the tranceive phase assumption for CSI-EPT and show electrical properties maps reconstructed from measured data obtained using a standard 3T birdcage body coil setup. Methods: The existing CSI-EPT algorithm is reformulated to use the transceive phase rather than relying on the transceive phase assumption. Furthermore, the radio frequency (RF)-shield is numerically implemented to accurately model the RF fields inside the MRI scanner. We verify that the reformulated two-dimensional (2D) CSI-EPT algorithm can reconstruct electrical properties maps given 2D electromagnetic simulations. Afterward, the algorithm is tested with three-dimensional (3D) FDTD simulations to investigate if the 2D CSI-EPT can retrieve the electrical properties for 3D RF fields. Finally, an MR experiment at 3T with a phantom is performed. Results: From the results of the 2D simulations, it is seen that CSI-EPT can reconstruct the electrical properties using MRI accessible quantities. For 3D simulations, it is observed that the electrical properties are underestimated, nonetheless, CSI-EPT has a lower standard deviation than the standard Helmholtz based methods. Finally, the first CSI-EPT reconstructions based on measured data are presented showing comparable accuracy and precision to reconstructions based on simulated data, and demonstrating the feasibility of CSI-EPT. Conclusions: The CSI-EPT algorithm was rewritten to use MRI accessible quantities. This allows for CSI-EPT to fully exploit the benefits of the higher static magnetic field strengths with a standard quadrature birdcage coil setup.

PurposeTo develop a rapid and accurate MRI phase unwrapping technique for challenging phase topographies encountered at high magnetic fields, around metal implants or post-operative cavities, that is sufficiently fast to be applied to large group studies including Quantitative Susceptibility Mapping and functional MRI (with phase-based distortion correction).MethodsThe proposed path-following phase unwrapping algorithm, ROMEO, estimates the coherence of the signal both in space - using MRI magnitude and phase information - and over time, assuming approximately linear temporal phase evolution. This information is combined to form a quality map that guides the unwrapping along a three-dimensional path through the object using a computationally efficient minimum spanning tree algorithm. ROMEO was tested against the two most commonly used exact phase unwrapping methods: PRELUDE and BEST PATH in simulated topographies and at several field strengths: in 3 T and 7 T in vivo human head images and 9.4 T ex vivo rat head images.ResultsROMEO was more reliable than PRELUDE and BEST PATH, yielding unwrapping results with excellent temporal stability for multi-echo or multi-time-point data. ROMEO does not require image masking and delivers results within seconds even in large, highly wrapped multi-echo datasets (e.g. 9 seconds for a 7 T head dataset with 31 echoes and a 208 x 208 x 96 matrix size).ConclusionOverall, ROMEO was both faster and more accurate than PRELUDE and BEST PATH delivering exact results within seconds, which is well below typical image acquisition times, enabling potential on-console application.

Graphic abstract Lack of data is an obvious limitation to what can be modelled. However, aggregate data in the form of means and possibly (co)variances, as well as previously published pharmacometric models, are often available. Being able to use all available data is desirable, and therefore this paper will outline several methods for using aggregate data as the basis of parameter estimation. The presented methods can be used for estimation of parameters from aggregate data, and as a computationally efficient alternative for the stochastic simulation and estimation procedure. They also allow for population PK/PD optimal design in the case when the data-generating model is different from the data-analytic model, a scenario for which no solutions have previously been available. Mathematical analysis and computational results confirm that the aggregate-data FO algorithm converges to the same estimates as the individual-data FO and yields near-identical standard errors when used in optimal design. The aggregate-data MC algorithm will asymptotically converge to the exactly correct parameter estimates if the data-generating model is the same as the data-analytic model. The performance of the aggregate-data methods were also compared to stochastic simulations and estimations (SSEs) when the data-generating model is different from the data-analytic model. The aggregate-data FO optimal design correctly predicted the sampling distributions of 200 models fitted to simulated datasets with the individual-data FO method. Supplementary Information The online version contains supplementary material available at 10.1007/s10928-021-09760-1.

Significance: Fourier ptychography microscopy (FPM) is a computational optical imaging technology that employs angularly varying illuminations and a phase retrieval algorithm to achieve a wide field of view and high-resolution imaging simultaneously. In the FPM, LED position error will reduce the quality of the reconstructed high-resolution image. To correct the LED positions, current methods consider each of the LED positions as independent and use an optimization algorithm to get each of the positions. When the positional misalignment is large or the search position falls into a local optimal value, the current methods may lack stability and accuracy. Aim: We improve the model of the LED position and propose an accurate and stable two-step correction scheme (tcFPM) to calibrate the LED position error. Approach: The improved LED positions model combines the overall offset, which represents the relative deviation of the LED array and the optical axis, with the slight deviation of each LED’s independent position. In the tcFPM, the overall offset of the LED array is corrected at first, which obtains an approximate value of the overall offset of the LED array. Then the position of each LED is precisely adjusted, which obtains the slight offset of each LED. Results: This LED position error model is more in line with the actual situation. The simulation and experimental results show that the method has high accuracy in correcting the LED position. Furthermore, the reconstruction process of tcFPM is more stable and significantly improves the quality of the reconstruction results, which is compared with some LED position error correction methods. Conclusions: An LED position error correction technology is proposed, which has a stable iterative process and improves the reconstruction accuracy of complex amplitude.

Background Margin reflex distance 1 (MRD1), margin reflex distance 2 (MRD2), and levator muscle function (LF) are crucial metrics for ptosis evaluation and management. However, manual measurements of MRD1, MRD2, and LF are time-consuming, subjective, and prone to human error. Smartphone-based artificial intelligence (AI) image processing is a potential solution to overcome these limitations. Objective We propose the first smartphone-based AI-assisted image processing algorithm for MRD1, MRD2, and LF measurements. Methods This observational study included 822 eyes of 411 volunteers aged over 18 years from August 1, 2020, to April 30, 2021. Six orbital photographs (bilateral primary gaze, up-gaze, and down-gaze) were taken using a smartphone (iPhone 11 Pro Max). The gold-standard measurements and normalized eye photographs were obtained from these orbital photographs and compiled using AI-assisted software to create MRD1, MRD2, and LF models. Results The Pearson correlation coefficients between the gold-standard measurements and the predicted values obtained with the MRD1 and MRD2 models were excellent (r=0.91 and 0.88, respectively) and that obtained with the LF model was good (r=0.73). The intraclass correlation coefficient demonstrated excellent agreement between the gold-standard measurements and the values predicted by the MRD1 and MRD2 models (0.90 and 0.84, respectively), and substantial agreement with the LF model (0.69). The mean absolute errors were 0.35 mm, 0.37 mm, and 1.06 mm for the MRD1, MRD2, and LF models, respectively. The 95% limits of agreement were –0.94 to 0.94 mm for the MRD1 model, –0.92 to 1.03 mm for the MRD2 model, and –0.63 to 2.53 mm for the LF model. Conclusions We developed the first smartphone-based AI-assisted image processing algorithm for eyelid measurements. MRD1, MRD2, and LF measures can be taken in a quick, objective, and convenient manner. Furthermore, by using a smartphone, the examiner can check these measurements anywhere and at any time, which facilitates data collection.

Significance: As linear array transducers are widely used in clinical ultrasound imaging, photoacoustic tomography (PAT) with linear arrays is similarly suitable for clinical applications. However, due to the limited-view problem, a linear array has limited performance and leads to artifacts and blurring, which has hindered its broader application. There is a need to address the limited-view problem in PAT imaging with linear arrays. Aim: We investigate potential approaches for improving PAT reconstruction from linear array, by optimizing the detection geometry and implementing iterative reconstruction. Approach: PAT imaging with a single-array, dual-probe configurations in parallel-shape and L-shape, and square-shape configuration are compared in simulations and phantom experiments. An iterative model-based algorithm based on the variance-reduced stochastic gradient descent (VR-SGD) method is implemented. The optimum configuration found in simulation is validated on phantom experiments. Results: PAT imaging with dual-probe detection and VR-SGD algorithm is found to improve the limited-view problem compared to a single probe and provide comparable performance as full-view geometry in simulation. This configuration is validated in experiments where more complete structure is obtained with reduced artifacts compared with a single array. Conclusions: PAT with dual-probe detection and iterative reconstruction is a promising solution to the limited-view problem of linear arrays.

This work was supported by the EPSRC (Grant No. EP/K503162/1). Significance : Optical microscopy is characterized by the ability to get high resolution, below 1 μm, high contrast, functional and quantitative images. The use of shaped illumination, such as with lightsheet microscopy, has led to greater three-dimensional isotropic resolution with low phototoxicity. However, in most complex samples and tissues, optical imaging is limited by scattering. Many solutions to this issue have been proposed, from using passive approaches such as Bessel beam illumination to active methods incorporating aberration correction, but making fair comparisons between different approaches has proven to be challenging. Aim : We present a phase-encoded Monte Carlo radiation transfer algorithm (φMC) capable of comparing the merits of different illumination strategies or predicting the performance of an individual approach. Approach : We show that φMC is capable of modeling interference phenomena such as Gaussian or Bessel beams and compare the model with experiment. Results : Using this verified model, we show that, for a sample with homogeneously distributed scatterers, there is no inherent advantage to illuminating a sample with a conical wave (Bessel beam) instead of a spherical wave (Gaussian beam), except for maintaining a greater depth of focus. Conclusion : φMC is adaptable to any illumination geometry, sample property, or beam type (such as fractal or layered scatterer distribution) and as such provides a powerful predictive tool for optical imaging in thick samples. Publisher PDF

Significance: Quantitative stiffness information can be a powerful aid for tumor or fibrosis diagnosis. Currently, very promising elastography approaches developed for non-contact biomedical imaging are based on transient shear-waves imaging. Transient elastography offers quantitative stiffness information by tracking the propagation of a wave front. The most common method used to compute stiffness from the acquired propagation movie is based on shear-wave time-of-flight calculations. Aim: We introduce an approach to transient shear-wave elastography with spatially coherent sources, able to yield full-field quantitative stiffness maps with reduced artifacts compared to typical artifacts observed in time-of-flight. Approach: A noise-correlation algorithm developed for passive elastography is adapted to spatially coherent narrow or any band sources. This noise-correlation-inspired (NCi) method is employed in parallel with a classic time-of-flight approach. Testing is done on simulation images, experimental validation is conducted with a digital holography setup on controlled homogeneous samples, and full-field quantitative stiffness maps are presented for heterogeneous samples and ex-vivo biological tissues. Results: The NCi approach is first validated on simulations images. Stiffness images processed by the NCi approach on simulated inclusions display significantly less artifacts than with a time-of-flight reconstruction. The adaptability of the NCi algorithm to narrow or any band shear-wave sources was tested successfully. Experimental testing on homogeneous samples demonstrates similar values for both the time-of-flight and the NCi approach. Soft inclusions in agarose sample could be resolved using the NCi method and feasibility on ex-vivo biological tissues is presented. Conclusions: The presented NCi approach was successful in computing quantitative full-field stiffness maps with narrow and broadband source signals on simulation and experimental images from a digital holography setup. Results in heterogeneous media show that the NCi approach could provide stiffness maps with less artifacts than with time-of-flight, demonstrating that a NCi algorithm is a promising approach for shear-wave transient elastography with spatially coherent sources.

Significance: Screening and early detection of oral potentially malignant lesions (OPMLs) are of great significance in reducing the mortality rates associated with head and neck malignancies. Intra-oral multispectral optical imaging of tissues in conjunction with cloud-based machine learning (CBML) can be used to detect oral precancers at the point-of-care (POC) and guide the clinician to the most malignant site for biopsy. Aim: Develop a bimodal multispectral imaging system (BMIS) combining tissue autofluorescence and diffuse reflectance (DR) for mapping changes in oxygenated hemoglobin (HbO2) absorption in the oral mucosa, quantifying tissue abnormalities, and guiding biopsies. Approach: The hand-held widefield BMIS consisting of LEDs emitting at 405, 545, 575, and 610 nm, 5MPx monochrome camera, and proprietary Windows-based software was developed for image capture, processing, and analytics. The DR image ratio (R610/R545) was compared with pathologic classification to develop a CBML algorithm for real-time assessment of tissue status at the POC. Results: Sensitivity of 97.5% and specificity of 92.5% were achieved for discrimination of OPML from patient normal in 40 sites, whereas 82% sensitivity and 96.6% specificity were obtained for discrimination of abnormal (OPML + SCC) in 89 sites. Site-specific algorithms derived for buccal mucosa (27 sites) showed improved sensitivity and specificity of 96.3% for discrimination of OPML from normal. Conclusions: Assessment of oral cancer risk is possible by mapping of HbO2 absorption in tissues, and the BMIS system developed appears to be suitable for biopsy guidance and early detection of oral cancers.

A new scaling program is presented with new features to support multi-sweep workflows and analysis within the DIALS software package., In processing X-ray diffraction data, the intensities obtained from integration of the diffraction images must be corrected for experimental effects in order to place all intensities on a common scale both within and between data collections. Scaling corrects for effects such as changes in sample illumination, absorption and, to some extent, global radiation damage that cause the measured intensities of symmetry-equivalent observations to differ throughout a data set. This necessarily requires a prior evaluation of the point-group symmetry of the crystal. This paper describes and evaluates the scaling algorithms implemented within the DIALS data-processing package and demonstrates the effectiveness and key features of the implementation on example macromolecular crystallographic rotation data. In particular, the scaling algorithms enable new workflows for the scaling of multi-crystal or multi-sweep data sets, providing the analysis required to support current trends towards collecting data from ever-smaller samples. In addition, the implementation of a free-set validation method is discussed, which allows the quantification of the suitability of scaling-model and algorithm choices.

PurposeTo develop an efficient algorithm for multi‐component analysis of magnetic resonance fingerprinting (MRF) data without making a priori assumptions about the exact number of tissues or their relaxation properties.MethodsDifferent tissues or components within a voxel are potentially separable in MRF because of their distinct signal evolutions. The observed signal evolution in each voxel can be described as a linear combination of the signals for each component with a non‐negative weight. An assumption that only a small number of components are present in the measured field of view is usually imposed in the interpretation of multi‐component data. In this work, a joint sparsity constraint is introduced to utilize this additional prior knowledge in the multi‐component analysis of MRF data. A new algorithm combining joint sparsity and non‐negativity constraints is proposed and compared to state‐of‐the‐art multi‐component MRF approaches in simulations and brain MRF scans of 11 healthy volunteers.ResultsSimulations and in vivo measurements show reduced noise in the estimated tissue fraction maps compared to previously proposed methods. Applying the proposed algorithm to the brain data resulted in 4 or 5 components, which could be attributed to different brain structures, consistent with previous multi‐component MRF publications.ConclusionsThe proposed algorithm is faster than previously proposed methods for multi‐component MRF and the simulations suggest improved accuracy and precision of the estimated weights. The results are easier to interpret compared to voxel‐wise methods, which combined with the improved speed is an important step toward clinical evaluation of multi‐component MRF.

Background The 6-min walk test (6MWT) is a convenient method for assessing functional capacity in patients with cardiopulmonary conditions. It is usually performed in the context of a hospital clinic and thus requires the involvement of hospital staff and facilities, with their associated costs. Objective This study aimed to develop a mobile phone–based system that allows patients to perform the 6MWT in the community. Methods We developed 2 algorithms to compute the distance walked during a 6MWT using sensors embedded in a mobile phone. One algorithm makes use of the global positioning system to track the location of the phone when outdoors and hence computes the distance travelled. The other algorithm is meant to be used indoors and exploits the inertial sensors built into the phone to detect U-turns when patients walk back and forth along a corridor of fixed length. We included these algorithms in a mobile phone app, integrated with wireless pulse oximeters and a back-end server. We performed Bland-Altman analysis of the difference between the distances estimated by the phone and by a reference trundle wheel on 49 indoor tests and 30 outdoor tests, with 11 different mobile phones (both Apple iOS and Google Android operating systems). We also assessed usability aspects related to the app in a discussion group with patients and clinicians using a technology acceptance model to guide discussion. Results The mean difference between the mobile phone-estimated distances and the reference values was −2.013 m (SD 7.84 m) for the indoor algorithm and −0.80 m (SD 18.56 m) for the outdoor algorithm. The absolute maximum difference was, in both cases, below the clinically significant threshold. A total of 2 pulmonary hypertension patients, 1 cardiologist, 2 physiologists, and 1 nurse took part in the discussion group, where issues arising from the use of the 6MWT in hospital were identified. The app was demonstrated to be usable, and the 2 patients were keen to use it in the long term. Conclusions The system described in this paper allows patients to perform the 6MWT at a place of their convenience. In addition, the use of pulse oximetry allows more information to be generated about the patient’s health status and, possibly, be more relevant to the real-life impact of their condition. Preliminary assessment has shown that the developed 6MWT app is highly accurate and well accepted by its users. Further tests are needed to assess its clinical value.

In this paper, we applied a novel method for the detection of Alzheimer's disease (AD) based on a structural magnetic resonance imaging (sMRI) dataset. Specifically, the method involved a new classification algorithm of machine learning, named Generalized Split Linearized Bregman Iteration (GSplit LBI). It combines logistic regression and structural sparsity regularizations. In the study, 57 AD patients and 47 normal controls (NCs) were enrolled. We first extracted the entire brain gray matter volume values of all subjects and then used GSplit LBI to build a predictive classification model with a 10-fold full cross-validation method. The model accuracy achieved 90.44%. To further verify which voxels in the dataset have greater impact on the prediction results, we ranked the weight parameters and obtained the top 6% of the model parameters. To verify the generalization of model prediction and the stability of feature selection, we performed a cross-test on the Alzheimer's Disease Neuroimaging Initiative (ADNI) and a Chinese dataset and achieved good performances on different cohorts. Conclusively, based on the sMRI dataset, our algorithm not only had good performance in a local cohort with high accuracy but also had good generalization of model prediction and stability of feature selection in different cohorts.

A new pipeline to solve structures by molecular replacement with ideal protein fragments is described and benchmarked against two test sets of mixed α/β and all-β folds at relatively high resolution., Correctly positioning ideal protein fragments by molecular replacement presents an attractive method for obtaining preliminary phases when no template structure for molecular replacement is available. This has been exploited in several existing pipelines. This paper presents a new pipeline, named Fragon, in which fragments (ideal α-helices or β-strands) are placed using Phaser and the phases calculated from these coordinates are then improved by the density-modification methods provided by ACORN. The reliable scoring algorithm provided by ACORN identifies success. In these cases, the resulting phases are usually of sufficient quality to enable automated model building of the entire structure. Fragon was evaluated against two test sets comprising mixed α/β folds and all-β folds at resolutions between 1.0 and 1.7 Å. Success rates of 61% for the mixed α/β test set and 30% for the all-β test set were achieved. In almost 70% of successful runs, fragment placement and density modification took less than 30 min on relatively modest four-core desktop computers. In all successful runs the best set of phases enabled automated model building with ARP/wARP to complete the structure.

The purpose of the present study was to reconstruct the energy spectrum of a poly-energetic neutron source using an algorithm developed based on an Adaptive Neuro-Fuzzy Inference System (ANFIS). ANFIS is a kind of artificial neural network based on the Takagi–Sugeno fuzzy inference system. The ANFIS algorithm uses the advantages of both fuzzy inference systems and artificial neural networks to improve the effectiveness of algorithms in various applications such as modeling, control and classification. The neutron pulse height distributions used as input data in the training procedure for the ANFIS algorithm were obtained from the simulations performed by MCNPX-ESUT computational code (MCNPX-Energy engineering of Sharif University of Technology). Taking into account the normalization condition of each energy spectrum, 4300 neutron energy spectra were generated randomly. (The value in each bin was generated randomly, and finally a normalization of each generated energy spectrum was performed). The randomly generated neutron energy spectra were considered as output data of the developed ANFIS computational code in the training step. To calculate the neutron energy spectrum using conventional methods, an inverse problem with an approximately singular response matrix (with the determinant of the matrix close to zero) should be solved. The solution of the inverse problem using the conventional methods unfold neutron energy spectrum with low accuracy. Application of the iterative algorithms in the solution of such a problem, or utilizing the intelligent algorithms (in which there is no need to solve the problem), is usually preferred for unfolding of the energy spectrum. Therefore, the main reason for development of intelligent algorithms like ANFIS for unfolding of neutron energy spectra is to avoid solving the inverse problem. In the present study, the unfolded neutron energy spectra of 252Cf and 241Am-9Be neutron sources using the developed computational code were found to have excellent agreement with the reference data. Also, the unfolded energy spectra of the neutron sources as obtained using ANFIS were more accurate than the results reported from calculations performed using artificial neural networks in previously published papers.

N6-methyladenosine (m6A) is a prevalent RNA methylation modification involved in several biological processes. Hundreds or thousands of m6A sites identified from different species using high-throughput experiments provides a rich resource to construct in-silico approaches for identifying m6A sites. The existing m6A predictors are developed using conventional machine-learning (ML) algorithms and most are species-centric. In this paper, we develop a novel cross-species deep-learning classifier based on bidirectional Gated Recurrent Unit (BGRU) for the prediction of m6A sites. In comparison with conventional ML approaches, BGRU achieves outstanding performance for the Mammalia dataset that contains over fifty thousand m6A sites but inferior for the Saccharomyces cerevisiae dataset that covers around a thousand positives. The accuracy of BGRU is sensitive to the data size and the sensitivity is compensated by the integration of a random forest classifier with a novel encoding of enhanced nucleic acid content. The integrated approach dubbed as BGRU-based Ensemble RNA Methylation site Predictor (BERMP) has competitive performance in both cross-validation test and independent test. BERMP also outperforms existing m6A predictors for different species. Therefore, BERMP is a novel multi-species tool for identifying m6A sites with high confidence. This classifier is freely available at http://www.bioinfogo.org/bermp.

Objectives: To compare image quality and radiation dose of CT images reconstructed with model-based iterative reconstruction (MBIR) and hybrid-iterative (HIR) algorithm in oncologic patients. Methods: 125 oncologic patients underwent both contrast-enhanced low- (100 kV), and standard (120 kV) dose CT, were enrolled. Image quality was assessed by using a 4-point Likert scale. CT attenuation values, expressed in Hounsfield unit (HU), were recorded within a regions of interest (ROI) of liver, spleen, paraspinal muscle, aortic lumen, and subcutaneous fat tissue. Image noise, expressed as standard deviation (SD), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated. Radiation dose were analyzed. Paired Student’s t-test was used to compare all continuous variables. Results: The overall median score assessed as image quality for CT images with the MBIR algorithm was significantly higher in comparison with HIR [4 (range 3–4) vs 3 (3-4), p = 0.017]. CT attenuation values and SD were significantly higher and lower, respectively, in all anatomic districts in images reconstructed with MBIR in comparison with HIR ones (all p < 0.001). SNR and CNR values were higher in CT images reconstructed with MBIR, reaching a significant difference in all districts (all p < 0.001). Radiation dose were significantly lower in the MBIR group compared with the HIR group (p < 0.001). Conclusions: MBIR combined with low-kV setting allows an important dose reduction in whole-body CT imaging, reaching a better image quality both qualitatively and quantitatively. Advances in knowledge: MBIR with low-dose approach allows a reduction of dose exposure, maintaining high image quality, especially in patients which deserve a longlasting follow-up.

Background: Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030 and 10 CpG sites, respectively, were recently established to predict health outcomes and mortality. We aimed to compare and validate the predictive ability of these scores and frailty in relation to mortality in a population-based cohort of older adults (50-75 years at baseline) from Germany. Methods: DNA methylation in whole blood was measured by the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) and used to calculate the three methylation algorithms in two random subsets of the ESTHER cohort study (n = 741 and n = 1030). Frailty was assessed by a frailty index (FI) based on percentage of 34 selected deficits. Findings: During 14 years of follow-up, a total of 346 deaths were observed. AgeAccelPheno, AgeAccelGrim, MRscore and FI were positively correlated. Although each of them was strongly and independently associated with mortality, the association was strongest for MRscore [adjusted hazard ratio (95% CI) per SD increase = 1·73 (1·46-2·06]. Harrell’s C-statistic was 0·706 for a model predicting mortality by age and sex alone and increased to 0·752 in a model including MRscore and the FI. Interpretation: The combination of a DNA methylation score based on 10 CpGs only and an easy to ascertain frailty index may strongly enhance mortality prediction beyond age and sex. Funding Information: The ESTHER study was funded by grants from the Baden-Wurttemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland State Ministry of Health, Social Affairs, Women and the Family (Saarbrucken, Germany). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: The ESTHER study was approved by the ethics committees of the medical faculty of the University of Heidelberg and the medical board of the state of Saarland. Written informed consent was obtained from each participant.

A data-processing pipeline to solve structures from tomograms of protein nanocrystals is presented and validated using simulated crystals. The robustness of this workflow to radiation damage is assessed to investigate optimal data-collection strategies., Structure-determination methods are needed to resolve the atomic details that underlie protein function. X-ray crystallography has provided most of our knowledge of protein structure, but is constrained by the need for large, well ordered crystals and the loss of phase information. The rapidly developing methods of serial femtosecond crystallography, micro-electron diffraction and single-particle reconstruction circumvent the first of these limitations by enabling data collection from nanocrystals or purified proteins. However, the first two methods also suffer from the phase problem, while many proteins fall below the molecular-weight threshold required for single-particle reconstruction. Cryo-electron tomography of protein nanocrystals has the potential to overcome these obstacles of mainstream structure-determination methods. Here, a data-processing scheme is presented that combines routines from X-ray crystallography and new algorithms that have been developed to solve structures from tomograms of nanocrystals. This pipeline handles image-processing challenges specific to tomographic sampling of periodic specimens and is validated using simulated crystals. The tolerance of this workflow to the effects of radiation damage is also assessed. The simulations indicate a trade-off between a wider tilt range to facilitate merging data from multiple tomograms and a smaller tilt increment to improve phase accuracy. Since phase errors, but not merging errors, can be overcome with additional data sets, these results recommend distributing the dose over a wide angular range rather than using a finer sampling interval to solve the protein structure.

Multiple myeloma (MM) is a malignancy with varying survival outcomes and drivers of disease progression. Existing MM staging tools were developed using data from newly diagnosed patients. As patient characteristics and disease-related factors change between diagnosis and the initiation of second-line (2L) treatment, an unmet need exists for a tool that can evaluate risk of death at first relapse. We have developed a risk stratification algorithm (RSA) using data from patients with MM who were at 2L. Hazard ratios for independent predictors of overall survival (OS) were derived from a Cox models, and individual patient scores were calculated for total risk. K-adaptive partitioning for survival was used to stratify patients into groups based on their scores. Relative risk doubled with ascending risk group; median OSs for patients in group 1 (lowest risk)-4 (highest risk) were 61·6, 29·6, 14·2 and 5·9 months, respectively. Differences in OS between risk groups were significant. Similar stratification was observed when the RSA was applied to an external validation data set. In conclusion, we have developed a validated RSA that can quantify total risk, frailty risk and disease aggressiveness risk, and stratify patients with MM at 2L into groups with profoundly different survival expectations. ispartof: BRITISH JOURNAL OF HAEMATOLOGY vol:187 issue:4 pages:447-458 ispartof: location:England status: published

Recent advances in automated protein model building using ARP/wARP are presented. The new methods include machine-learning-enhanced sequence assignment and loop building using a fragment database., The performance of automated model building in crystal structure determination usually decreases with the resolution of the experimental data, and may result in fragmented models and incorrect side-chain assignment. Presented here are new methods for machine-learning-based docking of main-chain fragments to the sequence and for their sequence-independent connection using a dedicated library of protein fragments. The combined use of these new methods noticeably increases sequence coverage and reduces fragmentation of the protein models automatically built with ARP/wARP.

Physiologically based pharmacokinetic (PBPK) models are an important type of systems model used commonly in drug development before commencement of first-in-human studies. Due to structural complexity, these models are not easily utilised for future data-driven population pharmacokinetic (PK) analyses that require simpler models. In the current study we aimed to explore and automate methods of simplifying PBPK models using a proper lumping technique. A linear 17-state PBPK model for fentanyl was identified from the literature. Four methods were developed to search the optimal lumped model, including full enumeration (the reference method), non-adaptive random search (NARS), scree plot plus NARS, and simulated annealing (SA). For exploratory purposes, it was required that the total area under the fentanyl arterial concentration–time curve (AUC) between the lumped and original models differ by 0.002% at maximum. In full enumeration, a 4-state lumped model satisfying the exploratory criterion was found. In NARS, a lumped model with the same number of lumped states was found, requiring a large number of random samples. The scree plot provided a starting lumped model to NARS and the search completed within a short time. In SA, a 4-state lumped model was consistently delivered. In simplify an existing linear fentanyl PBPK model, SA was found to be robust and the most efficient and may be suitable for general application to other larger-scale linear systems. Ultimately, simplified PBPK systems with fundamental mechanisms may be readily used for data-driven PK analyses. Electronic supplementary material The online version of this article (10.1007/s10928-019-09644-5) contains supplementary material, which is available to authorized users.

Objective: This study aims to present the diagnostic characteristics of multimodal intraoperative monitoring (IOM) in spinal deformity surgery and to define and categorise the neuromonitoring events, as well as propose an algorithm of action. Materials and Methods: We reviewed 1,155 consecutive patients (807 female, 348 male) who underwent deformity correction using standardised perioperative care, cortical/cervical somatosensory evoked potentials (SSEPs), and upper/lower limb transcranial electrical motor evoked potential (MEPs) by a single surgeon. The mean age at surgery was 13.8 years (range 10–23.3). We categorised IOM events as true, transient true, and false positive or negative. Diagnostic performance criteria were calculated. Results: The most common diagnosis was adolescent idiopathic scoliosis in 717 (62%) patients. We identified 3 true positive monitoring events occurring in 2 patients (0.17%), 8 transient true positive (0.69%), and 8 transient false positive events (0.69%). There were no false negative events and no patient had postoperative neurological complications. The multimodal IOM technique had a sensitivity of 100%, specificity of 99.3%, positive predictive value of 55.6%, and negative predictive value of 100%. Sensitivity was 100% for MEPs and multimodal monitoring compared to 20% for cortical or cervical SSEPs. The frequency of true or transient true positive events was higher (p = 0.07) in Scheuermann’s kyphosis (3/91 patients, 3.3%) compared to adolescent idiopathic scoliosis (6/717 patients, 0.84%). Conclusion: Multimodal IOM is highly sensitive and specific for spinal cord injury. This technique is reliable for the assessment of the condition of the spinal cord during major deformity surgery. We propose an algorithm of intraoperative action to allow close cooperation between the surgical, anaesthetic, and neurophysiology teams and to prevent neurological deficits.

Motivation Data splitting is a fundamental step for building classification models with spectral data, especially in biomedical applications. This approach is performed following pre-processing and prior to model construction, and consists of dividing the samples into at least training and test sets; herein, the training set is used for model construction and the test set for model validation. Some of the most-used methodologies for data splitting are the random selection (RS) and the Kennard-Stone (KS) algorithms; here, the former works based on a random splitting process and the latter is based on the calculation of the Euclidian distance between the samples. We propose an algorithm called the Morais-Lima-Martin (MLM) algorithm, as an alternative method to improve data splitting in classification models. MLM is a modification of KS algorithm by adding a random-mutation factor. Results RS, KS and MLM performance are compared in simulated and six real-world biospectroscopic applications using principal component analysis linear discriminant analysis (PCA-LDA). MLM generated a better predictive performance in comparison with RS and KS algorithms, in particular regarding sensitivity and specificity values. Classification is found to be more well-equilibrated using MLM. RS showed the poorest predictive response, followed by KS which showed good accuracy towards prediction, but relatively unbalanced sensitivities and specificities. These findings demonstrate the potential of this new MLM algorithm as a sample selection method for classification applications in comparison with other regular methods often applied in this type of data. Availability and implementation MLM algorithm is freely available for MATLAB at https://doi.org/10.6084/m9.figshare.7393517.v1.

Background Skin cancer (SC), especially melanoma, is a growing public health burden. Experimental studies have indicated a potential diagnostic role for deep learning (DL) algorithms in identifying SC at varying sensitivities. Previously, it was demonstrated that diagnostics by dermoscopy are improved by applying an additional sonification (data to sound waves conversion) layer on DL algorithms. The aim of the study was to determine the impact of image quality on accuracy of diagnosis by sonification employing a rudimentary skin magnifier with polarized light (SMP). Methods Dermoscopy images acquired by SMP were processed by a first deep learning algorithm and sonified. Audio output was further analyzed by a different secondary DL. Study criteria outcomes of SMP were specificity and sensitivity, which were further processed by a F2-score, i.e. applying a twice extra weight to sensitivity over positive predictive values. Findings Patients (n = 73) fulfilling inclusion criteria were referred to biopsy. SMP analysis metrics resulted in a receiver operator characteristic curve AUC's of 0.814 (95% CI, 0.798–0.831). SMP achieved a F2-score sensitivity of 91.7%, specificity of 41.8% and positive predictive value of 57.3%. Diagnosing the same set of patients' lesions by an advanced dermoscope resulted in a F2-score sensitivity of 89.5%, specificity of 57.8% and a positive predictive value of 59.9% (P=NS). Interpretation DL processing of dermoscopic images followed by sonification results in an accurate diagnostic output for SMP, implying that the quality of the dermoscope is not the major factor influencing DL diagnosis of skin cancer. Present system might assist all healthcare providers as a feasible computer-assisted detection system. Fund Bostel Technologies. Trial Registration clinicaltrials.gov Identifier: NCT03362138

In this brief communication, which complements the EEG reference review (Yao et al. in Brain Topogr, 2019), we provide the mathematical derivations that show: (1) any EEG reference admits the general form of a linear transformation of the ideal multichannel EEG potentials with reference to infinity; (2) the average reference (AR), the reference electrode standardization technique (REST), and its regularized version (rREST) are solving the linear inverse problems that can be derived from both the maximum likelihood estimate (MLE) and the Bayesian theory; however, REST is based on more informative prior/constraint of volume conduction than that of AR; (3) we show for the first time that REST is also a unipolar reference (UR), allowing us to define a general family of URs with unified notations; (4) some notable properties of URs are 'no memory', 'rank deficient by 1', and 'orthogonal projector centering'; (5) we also point out here, for the first time, that rREST provides the optimal interpolating function that can be used when the reference channel is missing or the 'bad' channels are rejected. The derivations and properties imply that: (a) any two URs can transform to each other and referencing with URs multiple times will not accumulate artifacts; (b) whatever URs the EEG data was previously transformed with, the minimum norm solution to the reference problem will be REST and AR with and without modeling volume conduction, respectively; (c) the MLE and the Bayesian theory show the theoretical optimality of REST. The advantages and limitations of AR and REST are discussed to guide readers for their proper use.

Bridging fundamental approaches to model optimization for pharmacometricians, systems pharmacologists and statisticians is a critical issue. These fields rely primarily on Maximum Likelihood and Extended Least Squares metrics with iterative estimation of parameters. Our research combines adaptive chaos synchronization and grid search to estimate physiological and pharmacological systems with emergent properties by exploring deterministic methods that are more appropriate and have potentially superior performance than classical numerical approaches, which minimize the sum of squares or maximize the likelihood. We illustrate these issues with an established model of cortisol in human with nonlinear dynamics. The model describes cortisol kinetics over time, including its chaotic oscillations, by a delay differential equation. We demonstrate that chaos synchronization helps to avoid the tendency of the gradient-based optimization algorithms to end up in a local minimum. The subsequent analysis illustrates that the hybrid adaptive chaos synchronization for estimation of linear parameters with coarse-to-fine grid search for optimal values of non-linear parameters can be applied iteratively to accurately estimate parameters and effectively track trajectories for a wide class of noisy chaotic systems. Electronic supplementary material The online version of this article (10.1007/s10928-019-09629-4) contains supplementary material, which is available to authorized users.

Background: Early diagnosis of skin cancer lesions by dermoscopy, the gold standard in dermatological imaging, calls for a diagnostic upscale. The aim of the study was to improve the accuracy of dermoscopic skin cancer diagnosis through use of novel deep learning (DL) algorithms. An additional sonification-derived diagnostic layer was added to the visual classification to increase sensitivity. Methods: Two parallel studies were conducted: a laboratory retrospective study (LABS, n = 482 biopsies) and a non-interventional prospective observational study (OBS, n = 63 biopsies). A training data set of biopsy-verified reports, normal and cancerous skin lesions (n = 3954), were used to develop a DL classifier exploring visual features (System A). The outputs of the classifier were sonified, i.e. data conversion into sound (System B). Derived sound files were analyzed by a second machine learning classifier, either as raw audio (LABS, OBS) or following conversion into spectrograms (LABS) and by image analysis and human heuristics (OBS). The OBS criteria outcomes were System A specificity and System B sensitivity as raw sounds, spectrogram areas or heuristics. Findings: LABS employed dermoscopies, half benign half malignant, and compared the accuracy of Systems A and B. System A algorithm resulted in a ROC AUC of 0.976 (95% CI, 0.965–0.987). Secondary machine learning analysis of raw sound, FFT and Spectrogram ROC curves resulted in AUC's of 0.931 (95% CI 0.881–0.981), 0.90 (95% CI 0.838–0.963) and 0.988 (CI 95% 0.973–1.001), respectively. OBS analysis of raw sound dermoscopies by the secondary machine learning resulted in a ROC AUC of 0.819 (95% CI, 0.7956 to 0.8406). OBS image analysis of AUC for spectrograms displayed a ROC AUC of 0.808 (CI 95% 0.6945 To 0.9208). By applying a heuristic analysis of Systems A and B a sensitivity of 86% and specificity of 91% were derived in the clinical study. Interpretation: Adding a second stage of processing, which includes a deep learning algorithm of sonification and heuristic inspection with machine learning, significantly improves diagnostic accuracy. A combined two-stage system is expected to assist clinical decisions and de-escalate the current trend of over-diagnosis of skin cancer lesions as pathological. Fund: Bostel Technologies.Trial Registration clinicaltrials.gov Identifier: NCT03362138 Keywords: Skin cancer, Deep learning, Sonification, Artificial intelligence, Dermoscopy, Melanoma, Telemedicine

Motivation Metagenomics is the study of genetic materials directly sampled from natural habitats. It has the potential to reveal previously hidden diversity of microscopic life largely due to the existence of highly parallel and low-cost next-generation sequencing technology. Conventional approaches align metagenomic reads onto known reference genomes to identify microbes in the sample. Since such a collection of reference genomes is very large, the approach often needs high-end computing machines with large memory which is not often available to researchers. Alternative approaches follow an alignment-free methodology where the presence of a microbe is predicted using the information about the unique k-mers present in the microbial genomes. However, such approaches suffer from high false positives due to trading off the value of k with the computational resources. In this article, we propose a highly efficient metagenomic sequence classification (MSC) algorithm that is a hybrid of both approaches. Instead of aligning reads to the full genomes, MSC aligns reads onto a set of carefully chosen, shorter and highly discriminating model sequences built from the unique k-mers of each of the reference sequences. Results Microbiome researchers are generally interested in two objectives of a taxonomic classifier: (i) to detect prevalence, i.e. the taxa present in a sample, and (ii) to estimate their relative abundances. MSC is primarily designed to detect prevalence and experimental results show that MSC is indeed a more effective and efficient algorithm compared to the other state-of-the-art algorithms in terms of accuracy, memory and runtime. Moreover, MSC outputs an approximate estimate of the abundances. Availability and implementation The implementations are freely available for non-commercial purposes. They can be downloaded from https://drive.google.com/open?id=1XirkAamkQ3ltWvI1W1igYQFusp9DHtVl.

Motivation Estimating haplotype frequencies from genotype data plays an important role in genetic analysis. In silico methods are usually computationally involved since phase information is not available. Due to tight linkage disequilibrium and low recombination rates, the number of haplotypes observed in human populations is far less than all the possibilities. This motivates us to solve the estimation problem by maximizing the sparsity of existing haplotypes. Here, we propose a new algorithm by applying the compressive sensing (CS) theory in the field of signal processing, compressive sensing haplotype inference (CSHAP), to solve the sparse representation of haplotype frequencies based on allele frequencies and between-allele co-variances. Results Our proposed approach can handle both individual genotype data and pooled DNA data with hundreds of loci. The CSHAP exhibits the same accuracy compared with the state-of-the-art methods, but runs several orders of magnitude faster. CSHAP can also handle with missing genotype data imputations efficiently. Availability and implementation The CSHAP is implemented in R, the source code and the testing datasets are available at http://home.ustc.edu.cn/∼zhouys/CSHAP/. Supplementary information Supplementary data are available at Bioinformatics online.

Respiratory motion management is a huge challenge in radiation therapy. Respiratory motion induces temporal anatomic changes that distort the tumor volume and its position. In this study, a markerless tumor-tracking algorithm was investigated by performing phase recognition during stereotactic body radiation therapy (SBRT) using four-dimensional cone-beam computer tomography (4D-CBCT) obtained at patient registration, and in-treatment cone-beam projection images. The data for 20 treatment sessions (five lung cancer patients) were selected for this study. Three of the patients were treated with conventional flattening filter (FF) beams, and the other two were treated with flattening filter-free (FFF) beams. Prior to treatment, 4D-CBCT was acquired to create the template projection images for 10 phases. In-treatment images were obtained at near real time during treatment. Template-based phase recognition was performed for 4D-CBCT re-projected templates using prior 4D-CBCT based phase recognition algorithm and was compared with the results generated by the Amsterdam Shroud (AS) technique. Visual verification technique was used for the verification of the phase recognition and AS technique at certain tumor-visible angles. Offline template matching analysis using the cross-correlation indicated that phase recognition performed using the prior 4D-CBCT and visual verification matched up to 97.5% in the case of FFF, and 95% in the case of FF, whereas the AS technique matched 83.5% with visual verification for FFF and 93% for FF. Markerless tumor tracking based on phase recognition using prior 4D-CBCT has been developed successfully. This is the first study that reports on the use of prior 4D-CBCT based on normalized cross-correlation technique for phase recognition.

Motivation How to partition a dataset into a set of distinct clusters is a ubiquitous and challenging problem. The fact that data vary widely in features such as cluster shape, cluster number, density distribution, background noise, outliers and degree of overlap, makes it difficult to find a single algorithm that can be broadly applied. One recent method, clusterdp, based on search of density peaks, can be applied successfully to cluster many kinds of data, but it is not fully automatic, and fails on some simple data distributions. Results We propose an alternative approach, clusterdv, which estimates density dips between points, and allows robust determination of cluster number and distribution across a wide range of data, without any manual parameter adjustment. We show that this method is able to solve a range of synthetic and experimental datasets, where the underlying structure is known, and identifies consistent and meaningful clusters in new behavioral data. Availability and implementation The clusterdv is implemented in Matlab. Its source code, together with example datasets are available on: https://github.com/jcbmarques/clusterdv. Supplementary information Supplementary data are available at Bioinformatics online.

Significance: Coherence, a fundamental property of waves and fields, plays a key role in photoacoustic image reconstruction. Previously, techniques such as short-lag spatial coherence (SLSC) and filtered delay, multiply, and sum (FDMAS) have utilized spatial coherence to improve the reconstructed resolution and contrast with respect to delay-and-sum (DAS). While SLSC uses spatial coherence directly as the imaging contrast, FDMAS employs spatial coherence implicitly. Despite being more robust against noise, both techniques have their own drawbacks: SLSC does not preserve a relative signal magnitude, and FDMAS shows a reduced contrast-to-noise ratio. Aim: To overcome these limitations, our aim is to develop a beamforming algorithm—generalized spatial coherence (GSC)—that unifies SLSC and FDMAS into a single equation and outperforms both beamformers. Approach: We demonstrated the application of GSC in photoacoustic computed tomography (PACT) through simulation and experiments and compared it to previous beamformers: DAS, FDMAS, and SLSC. Results: GSC outperforms the imaging metrics of previous state-of-the-art coherence-based beamformers in both simulation and experiments. Conclusions: GSC is an innovative reconstruction algorithm for PACT, which combines the strengths of FDMAS and SLSC expanding PACT’s applications.

Background The optimal management of neonatal post-hemorrhagic hydrocephalus (PHH) is still debated, though several treatment options have been proposed. In the last years, ventriculosubgaleal shunt (VSgS) and neuroendosdcopic lavage (NEL) have been proposed to overcome the drawbacks of more traditional options, such as external ventricular drainage and ventricular access device. Methods We retrospectively reviewed neonates affected by PHH treated at our institution since September 2012 to September 2020. Until 2017 patients received VSgS as initial treatment. After the introduction of NEL, this treatment option was offered to patients with large intraventricular clots. After NEL, VSgS was always placed. Primary VSgS was reserved to patients without significant intraventricular clots and critically ill patients that could not be transferred to the operating room and undergo a longer surgery. Results We collected 63 babies (38 males and 25 females) with mean gestational age of 27.8 ± 3.8SD weeks (range 23–38.5 weeks) and mean birthweight of 1199.7 ± 690.6 SD grams (range 500–3320 g). In 6 patients, hemorrhage occurred in the third trimester of gestation, while in the remaining cases hemorrhage complicated prematurity. This group included 37 inborn and 26 outborn babies. Intraventricular hemorrhage was classified as low grade (I–II according to modified Papile grading scale) in 7 cases, while in the remaining cases the grade of hemorrhage was III to IV. Mean age at first neurosurgical procedure was 32.2 ± 3.6SD weeks (range 25.4–40 weeks). Death due to prematurity occurred in 5 patients. First-line treatment was VSgS in 49 patients and NEL in the remaining 14 cases. Mean longevity of VSgS was 30.3 days (range 10–97 days) in patients finally requiring an additional treatment of hydrocephalus. Thirty-two patients required one to three redo VSgS. Interval from initial treatment to permanent shunt ranged from 14 to 312 days (mean 70.9 days). CSF infection was observed in 5 patients (7.9%). Shunt dependency was observed in 51 out of 58 surviving patients, while 7 cases remained shunt-free at the last follow-up. Multiloculated hydrocephalus was observed in 14 cases. Among these, only one patient initially received NEL and was complicated by isolated trapped temporal horn. Conclusions VSgS and NEL are two effective treatment options in the management of PHH. Both procedures should be part of the neurosurgical armamentarium to deal with PHH, since they offer specific advantages in selected patients. A treatment algorithm combining these two options may reduce the infectious risk and the risk of multiloculated hydrocephalus.

Objective To create a treatment algorithm for focal grade 3 or 4 cartilage defects of the knee using both classic and novel cartilage restoration techniques. Design A comprehensive review of the literature was performed highlighting classic as well as novel cartilage restoration techniques supported by clinical and/or basic science research and currently being employed by orthopedic surgeons. Results There is a high level of evidence to support the treatment of small to medium size lesions (2) without subchondral bone involvement with traditional techniques such as marrow stimulation, osteochondral autograft transplant (OAT), or osteochondral allograft transplant (OCA). Newer techniques such as autologous matrix-induced chondrogenesis and bone marrow aspirate concentrate implantation have also been shown to be effective in select studies. If subchondral bone loss is present OAT or OCA should be performed. For large lesions (>4 cm2), OCA or matrix autologous chondrocyte implantation (MACI) may be performed. OCA is preferred over MACI in the setting of subchondral bone involvement while cell-based modalities such as MACI or particulated juvenile allograft cartilage are preferred in the patellofemoral joint. Conclusions Numerous techniques exist for the orthopedic surgeon treating focal cartilage defects of the knee. Treatment strategies should be based on lesion size, lesion location, subchondral bone involvement, and the level of evidence supporting each technique in the literature.

Background Wearable devices are now widely available to collect continuous objective behavioral data from individuals and to measure sleep. Objective This study aims to introduce a pipeline to infer sleep onset, duration, and quality from raw accelerometer data and then quantify the relationships between derived sleep metrics and other variables of interest. Methods The pipeline released here for the deep phenotyping of sleep, as the DPSleep software package, uses a stepwise algorithm to detect missing data; within-individual, minute-based, spectral power percentiles of activity; and iterative, forward-and-backward–sliding windows to estimate the major Sleep Episode onset and offset. Software modules allow for manual quality control adjustment of the derived sleep features and correction for time zone changes. In this paper, we have illustrated the pipeline with data from participants studied for more than 200 days each. Results Actigraphy-based measures of sleep duration were associated with self-reported sleep quality ratings. Simultaneous measures of smartphone use and GPS location data support the validity of the sleep timing inferences and reveal how phone measures of sleep timing can differ from actigraphy data. Conclusions We discuss the use of DPSleep in relation to other available sleep estimation approaches and provide example use cases that include multi-dimensional, deep longitudinal phenotyping, extended measurement of dynamics associated with mental illness, and the possibility of combining wearable actigraphy and personal electronic device data (eg, smartphones and tablets) to measure individual differences across a wide range of behavioral variations in health and disease. A new open-source pipeline for deep phenotyping of sleep, DPSleep, analyzes raw accelerometer data from wearable devices and estimates sleep onset and offset while allowing for manual quality control adjustments.

A new algorithm for lattice reduction based on a series of directional and hyperplanar shears and driven by the decrease of the basis rhombicity is proposed. It can be used to reduce unit cells in dimension 3 and higher., A geometric method of lattice reduction based on cycles of directional and hyperplanar shears is presented. The deviation from cubicity at each step of the reduction is evaluated by a parameter called ‘basis rhombicity’ which is the sum of the absolute values of the elements of the metric tensor associated with the basis. The levels of reduction are quite similar to those obtained with the Lenstra–Lenstra–Lovász (LLL) algorithm, at least up to the moderate dimensions that have been tested (lower than 20). The method can be used to reduce unit cells attached to given hyperplanes.

Background Performing systematic reviews is a time-consuming and resource-intensive process. Objective We investigated whether a machine learning system could perform systematic reviews more efficiently. Methods All systematic reviews and meta-analyses of interventional randomized controlled trials cited in recent clinical guidelines from the American Diabetes Association, American College of Cardiology, American Heart Association (2 guidelines), and American Stroke Association were assessed. After reproducing the primary screening data set according to the published search strategy of each, we extracted correct articles (those actually reviewed) and incorrect articles (those not reviewed) from the data set. These 2 sets of articles were used to train a neural network–based artificial intelligence engine (Concept Encoder, Fronteo Inc). The primary endpoint was work saved over sampling at 95% recall (WSS@95%). Results Among 145 candidate reviews of randomized controlled trials, 8 reviews fulfilled the inclusion criteria. For these 8 reviews, the machine learning system significantly reduced the literature screening workload by at least 6-fold versus that of manual screening based on WSS@95%. When machine learning was initiated using 2 correct articles that were randomly selected by a researcher, a 10-fold reduction in workload was achieved versus that of manual screening based on the WSS@95% value, with high sensitivity for eligible studies. The area under the receiver operating characteristic curve increased dramatically every time the algorithm learned a correct article. Conclusions Concept Encoder achieved a 10-fold reduction of the screening workload for systematic review after learning from 2 randomly selected studies on the target topic. However, few meta-analyses of randomized controlled trials were included. Concept Encoder could facilitate the acquisition of evidence for clinical guidelines.

Background Hip fracture is the most common type of fracture in elderly individuals. Numerous deep learning (DL) algorithms for plain pelvic radiographs (PXRs) have been applied to improve the accuracy of hip fracture diagnosis. However, their efficacy is still undetermined. Objective The objective of this study is to develop and validate a human-algorithm integration (HAI) system to improve the accuracy of hip fracture diagnosis in a real clinical environment. Methods The HAI system with hip fracture detection ability was developed using a deep learning algorithm trained on trauma registry data and 3605 PXRs from August 2008 to December 2016. To compare their diagnostic performance before and after HAI system assistance using an independent testing dataset, 34 physicians were recruited. We analyzed the physicians’ accuracy, sensitivity, specificity, and agreement with the algorithm; we also performed subgroup analyses according to physician specialty and experience. Furthermore, we applied the HAI system in the emergency departments of different hospitals to validate its value in the real world. Results With the support of the algorithm, which achieved 91% accuracy, the diagnostic performance of physicians was significantly improved in the independent testing dataset, as was revealed by the sensitivity (physician alone, median 95%; HAI, median 99%; P Conclusions HAI currently impacts health care, and integrating this technology into emergency departments is feasible. The developed HAI system can enhance physicians’ hip fracture diagnostic performance.

Background Over the past decade, the emergence of several large federated clinical data networks has enabled researchers to access data on millions of patients at dozens of health care organizations. Typically, queries are broadcast to each of the sites in the network, which then return aggregate counts of the number of matching patients. However, because patients can receive care from multiple sites in the network, simply adding the numbers frequently double counts patients. Various methods such as the use of trusted third parties or secure multiparty computation have been proposed to link patient records across sites. However, they either have large trade-offs in accuracy and privacy or are not scalable to large networks. Objective This study aims to enable accurate estimates of the number of patients matching a federated query while providing strong guarantees on the amount of protected medical information revealed. Methods We introduce a novel probabilistic approach to running federated network queries. It combines an algorithm called HyperLogLog with obfuscation in the form of hashing, masking, and homomorphic encryption. It is tunable, in that it allows networks to balance accuracy versus privacy, and it is computationally efficient even for large networks. We built a user-friendly free open-source benchmarking platform to simulate federated queries in large hospital networks. Using this platform, we compare the accuracy, k-anonymity privacy risk (with k=10), and computational runtime of our algorithm with several existing techniques. Results In simulated queries matching 1 to 100 million patients in a 100-hospital network, our method was significantly more accurate than adding aggregate counts while maintaining k-anonymity. On average, it required a total of 12 kilobytes of data to be sent to the network hub and added only 5 milliseconds to the overall federated query runtime. This was orders of magnitude better than other approaches, which guaranteed the exact answer. Conclusions Using our method, it is possible to run highly accurate federated queries of clinical data repositories that both protect patient privacy and scale to large networks.