Refractory Hidradenitis Suppurativa: A Diagnosis to Consider.

Hidradenitis suppurativa is a chronic inflammatory disease associated with multiple comorbidities, and its association with lymphoma has recently been a topic of debate. However, it is still controversial whether this risk can be attributed to the disease itself or whether it has any relationship with immunosuppressive treatment. Here, we describe the case of a patient with severe perianal hidradenitis suppurativa treated with methotrexate and infliximab, whose exacerbation with persistence of severe symptoms refractory to adequate treatment led to the diagnosis of diffuse large non-Hodgkin B-cell lymphoma. It was decided to perform a colostomy to improve perianal sepsis, and immunochemotherapy was proposed.

A hidradenite supurativa é uma doença inflamatória crónica associada a múltiplas comorbilidades e a sua associação com doenças linfoproliferativas tem sido, recentemente, um tema de debate. No entanto, é controverso se esse risco pode ser atribuído à própria doença ou se tem relação com o tratamento imunossupressor. Descrevemos o caso de um doente com hidradenite supurativa perianal grave tratada com metotrexato e infliximab, cuja exacerbação com persistência de sintomas graves refratários ao tratamento adequado levou ao diagnóstico de linfoma não-Hodgkin difuso de grandes células B. Optou- se pela realização de colostomia para melhoria da sépsis perianal e início de imunoquimioterapia.

HiPhase: jointly phasing small, structural, and tandem repeat variants from HiFi sequencing.

MOTIVATION: In diploid organisms, phasing is the problem of assigning the alleles at heterozygous variants to one of two haplotypes. Reads from PacBio HiFi sequencing provide long, accurate observations that can be used as the basis for both calling and phasing variants. HiFi reads also excel at calling larger classes of variation, such as structural or tandem repeat variants. However, current phasing tools typically only phase small variants, leaving larger variants unphased. RESULTS: We developed HiPhase, a tool that jointly phases SNVs, indels, structural, and tandem repeat variants. The main benefits of HiPhase are (i) dual mode allele assignment for detecting large variants, (ii) a novel application of the A*-algorithm to phasing, and (iii) logic allowing phase blocks to span breaks caused by alignment issues around reference gaps and homozygous deletions. In our assessment, HiPhase produced an average phase block NG50 of 480 kb with 929 switchflip errors and fully phased 93.8% of genes, improving over the current state of the art. Additionally, HiPhase jointly phases SNVs, indels, structural, and tandem repeat variants and includes innate multi-threading, statistics gathering, and concurrent phased alignment output generation. AVAILABILITY AND IMPLEMENTATION: HiPhase is available as source code and a pre-compiled Linux binary with a user guide at https://github.com/PacificBiosciences/HiPhase.

Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition.

Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1, and RB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.

Identifying Clinical Predictors of Proliferative Sickle Cell Retinopathy.

PURPOSE: To identify systemic and/or ophthalmologic predictors of proliferative sickle retinopathy. METHODS: Cross-sectional study comparing clinical, laboratory, and structural choriorretinal aspects between sickle cell disease patients with and without proliferative retinopathy. Patients underwent complete systemic and ophthalmologic evaluation. Enhanced depth spectral domain optical coherence tomography with choroidal binarization and optic coherence tomography angiography were performed and choriorretinal vascular components were compared. RESULTS: Forty-five eyes from 45 sickle cell patients were included. Ninety-one percent of patients were diagnosed with sickle cell retinopathy, 29% with proliferative retinopathy. Mean corpuscular volume, lactate dehydrogenase, and percentage of fetal hemoglobin were reduced in the subgroup of patients with proliferative retinopathy when compared with patients without proliferative retinopathy (p ≤ 0.001; p = 0.04; p ≤ 0.001, respectively). The best predictor of proliferative retinopathy was mean corpuscular volume (AUC = 0.842; p = 0.001), followed by the percentage of fetal hemoglobin (AUC = 0.763, p = 0.009) and lactate dehydrogenase (AUC curve = 0.706; p = 0.039). No differences were found between groups in the quantitative analysis of retinal vascularization using OCTA and choroidal vascularization using OCT (p ≥ 0.05). CONCLUSION: Fetal hemoglobin and mean corpuscular volume may be good predictors of proliferative sickle retinopathy. The association between proliferative retinopathy and reduced levels of lactate dehydrogenase and mean corpuscular volume points to hypoxia and not hemolysis as a possible driving force in its pathophysiology.

Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.

Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.5%) hypermethylation events. We find that 80% of these events are allele-specific and predicted to cause loss of regulatory element activity. We demonstrate heritability of extreme hypermethylation including rare cis variants associated with short (~200 bp) and large hypermethylation events (>1 kb), respectively. We identify repeat expansions in proximal promoters predicting allelic gene silencing via hypermethylation and demonstrate allelic transcriptional events downstream. On average 30-40 rare hypermethylation tiles overlap rare disease genes per patient, providing indications for variation prioritization including a previously undiagnosed pathogenic allele in DIP2B causing global developmental delay. We propose that use of HiFi genome sequencing in unsolved rare disease cases will allow detection of unconventional diseases alleles due to loss of regulatory element activity.

Intracapsular Tonsillectomy Using Plasma Ablation Versus Total Tonsillectomy: A Systematic Literature Review and Meta-Analysis.

Objective: To determine whether intracapsular tonsillectomy, using plasma ablation, results in differences in postoperative patient outcomes to total tonsillectomy. Data Sources: A systematic review of two databases (Embase and PubMed) was conducted in March 2022 to identify published English-language randomized controlled trials and observational studies which provided a comparison between intracapsular tonsillectomy, using plasma ablation, and total tonsillectomy. Review Methods: Qualitative synthesis and meta-analysis were used to compare outcomes between techniques. Results: Seventeen studies were identified for inclusion. Across these, 1996 and 4565 patients underwent intracapsular and total tonsillectomy, respectively. Studies included 8 randomized controlled trials, 1 prospective cohort study, and 8 retrospective cohort studies. Time to pain free, time on analgesia, time to normal diet, and time to normal activity were significantly shorter with intracapsular tonsillectomy by on average 4.2 (95% confidence interval [CI] 1.5-5.9; p < .0001), 4.1 (95% CI 2.7-5.4; p < .0001), 3.5 (95% CI 1.7-5.4; p = .0002) and 2.8 (95% CI 1.6-4; p < .0001) days, respectively. Risk of posttonsillectomy hemorrhage was significantly lower following intracapsular tonsillectomy (relative risk [RR] 0.36; 95% CI 0.16-0.81; p = .0131); risk of posttonsillectomy hemorrhage requiring surgical management was lower but failed to reach significance (RR 0.52; 95% CI 0.19-1.39; p = .19). Conclusion: Intracapsular tonsillectomy using plasma ablation has similar efficacy in managing indications for tonsil surgery to total tonsillectomy while significantly reducing the postoperative morbidity and likelihood of posttonsillectomy hemorrhage experienced by patients, allowing them to return to their normal life faster.

Linking ammonium nitrate-aluminum (AN-AL) post-blast residues to pre-blast explosive materials using isotope ratio and trace elemental analysis for source attribution.

Forensic science practitioners are often called upon to attribute crimes using trace evidence, such as explosive remnants, with the ultimate goal of associating a crime with a suspect or suspects in order to prevent further attacks. The explosive charge is an attractive component for attribution in crimes involving explosives as there are limited pathways for acquisition. However, there is currently no capability to link an explosive charge to its source via post-blast trace residues using isotope ratios or trace elements. Here, we sought to determine if pre-blast attribution signatures are preserved after detonation and can be subsequently recovered and detected. A field study was conducted to recover samples of post-blast explosives from controlled detonations of ammonium nitrate-aluminum (AN-Al), which were then analyzed via isotope ratio mass spectrometry (IRMS) and inductively coupled plasma-mass spectrometry (ICP-MS) for quantitation and profiling of isotopes ratio and trace element signatures, respectively. Oxygen and nitrogen isotope ratios from AN-Al yielded some of the most promising results with considerable overlap within one standard deviation of the reference between the spreads of pre- and post-blast data. Trace element results from AN-Al support the findings in the isotope ratio data, with 26 elements detected in both pre- and post-blast samples, and several elements including B, Cd, Cr, Ni, Sn, V, and Zn showing considerable overlap. These preliminary results provide a proof-of-concept for the development of forensic examinations that can attribute signatures from post-blast debris to signatures in pre-blast explosive materials for use in future investigations.

Comparison of clinical outcomes of VISIONAIRE patient-specific instrumentation with conventional instrumentation in total knee arthroplasty: a systematic literature review and meta-analysis.

INTRODUCTION: Malalignment and resulting complications are major challenges in total knee arthroplasty (TKA) which patient-specific instrumentation (PSI) is proposed to alleviate. Previous PSI meta-analyses of TKA outcomes typically do not differentiate between PSI systems and assess relatively few outcomes, so the value of their findings is limited. VISIONAIRE™ cutting guides (Smith + Nephew Inc., Memphis, TN, USA) is a PSI system based on preoperative magnetic resonance and X-ray imaging. A systematic literature review (SLR) and meta-analysis, focussed specifically on VISIONAIRE, were conducted to assess TKA accuracy, intraoperative outcomes, and postoperative outcomes, compared with conventional instrumentation (CI). MATERIALS AND METHODS: The SLR was performed using PubMed, Embase, and Google Scholar databases to identify relevant studies published until March 2022. Depending on statistical heterogeneity, meta-analyses were performed for outcome measures with fixed effect (I2 < 50%) or random-effects models (I2 ≥ 50%). Dichotomous outcomes were reported as odds ratios and continuous outcomes were reported as mean differences. Descriptive analyses were performed for outcomes not amenable to meta-analysis. RESULTS: Outcomes for VISIONAIRE versus CI were reported in 25 studies. Compared with CI, VISIONAIRE reduced odds of mechanical outliers by 40% (p < 0.0001), with no statistically significant differences in odds of overall coronal, sagittal, or rotational plane component outliers. VISIONAIRE improved surgical efficiency (operating room, turnover, and tourniquet times reduced by 7.3% (p = 0.02), 42% (p = 0.022), and 15.9% (p = 0.01), respectively), lowering the odds of blood transfusion by 53% (p = 0.01) and shortening patients' hospital stays (11.1% reduction; p < 0.0001). There were no significant differences between groups in incidence of postoperative complications and (descriptively analyzed) return-to-function outcomes. CONCLUSION: Options for PSI in TKA differ substantially, and it is important to assess the outcomes of individual systems. The current findings suggest that VISIONAIRE guides can lead to improved alignment accuracy and surgical efficiency compared with CI, without compromising postoperative safety and return-to-function outcomes.

Considerations to comprehensive care for the older individual with myelofibrosis.

Over the last decade, we have witnessed a massive increase in available clinical agents, both in the clinical trial setting and following commercial use approval, directed to reduced life expectancy as well as the considerable symptom, splenic and anaemia burden associated with myelofibrosis. Given the median age of onset of the disease, coupled with an ageing population globally, we will be caring for an increasingly aged myelofibrosis cohort in future years. We will need to adapt our approach, emphasizing the holistic management of the older individual with myelofibrosis accordingly. Out with the pharmacological management of the disease, consideration needs to be given to interventions based on concurrent illness, comprehensive geriatric assessments, frailty, polypharmacy and drug-drug interactions, nutritional issues, psychological concerns (depression, anxiety or distress), cognitive decline and social/economic aspects. Within this review, we summarise available data addressing these issues, outline knowledge gaps and suggest a summative and holistic approach to the older individual with myelofibrosis.

REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats.

BACKGROUND: Expansions of short tandem repeats are the cause of many neurogenetic disorders including familial amyotrophic lateral sclerosis, Huntington disease, and many others. Multiple methods have been recently developed that can identify repeat expansions in whole genome or exome sequencing data. Despite the widely recognized need for visual assessment of variant calls in clinical settings, current computational tools lack the ability to produce such visualizations for repeat expansions. Expanded repeats are difficult to visualize because they correspond to large insertions relative to the reference genome and involve many misaligning and ambiguously aligning reads. RESULTS: We implemented REViewer, a computational method for visualization of sequencing data in genomic regions containing long repeat expansions and FlipBook, a companion image viewer designed for manual curation of large collections of REViewer images. To generate a read pileup, REViewer reconstructs local haplotype sequences and distributes reads to these haplotypes in a way that is most consistent with the fragment lengths and evenness of read coverage. To create appropriate training materials for onboarding new users, we performed a concordance study involving 12 scientists involved in short tandem repeat research. We used the results of this study to create a user guide that describes the basic principles of using REViewer as well as a guide to the typical features of read pileups that correspond to low confidence repeat genotype calls. Additionally, we demonstrated that REViewer can be used to annotate clinically relevant repeat interruptions by comparing visual assessment results of 44 FMR1 repeat alleles with the results of triplet repeat primed PCR. For 38 of these alleles, the results of visual assessment were consistent with triplet repeat primed PCR. CONCLUSIONS: Read pileup plots generated by REViewer offer an intuitive way to visualize sequencing data in regions containing long repeat expansions. Laboratories can use REViewer and FlipBook to assess the quality of repeat genotype calls as well as to visually detect interruptions or other imperfections in the repeat sequence and the surrounding flanking regions. REViewer and FlipBook are available under open-source licenses at https://github.com/illumina/REViewer and https://github.com/broadinstitute/flipbook respectively.

Elucidating the relationships between two automated handwriting feature quantification systems for multiple pairwise comparisons.

Recent advances in complex automated handwriting identification systems have led to a lack of understandability of these systems' computational processes and features by the forensic handwriting examiners that they are designed to support. To mitigate this issue, this research studied the relationship between two systems: FLASH ID® , an automated handwriting/black box system that uses measurements extracted from a static image of handwriting, and MovAlyzeR® , a system that captures kinematic features from pen strokes. For this study, 33 writers each wrote 60 phrases from the London Letter using cursive writing and handprinting, which led to thousands of sample pairs for analysis. The dissimilarities between pairs of samples were calculated using two score functions (one for each system). The observed results indicate that dissimilarity scores based on kinematic spatial-geometric pen stroke features (e.g., amplitude and slant) have a statistically significant relationship with dissimilarity scores obtained using static, graph-based features used by the FLASH ID® system. Similar relationships were observed for temporal features (e.g., duration and velocity) but not pen pressure, and for both handprinting and cursive samples. These results strongly imply that both the current implementation of FLASH ID® and MovAlyzeR® rely on similar features sets when measuring differences in pairs of handwritten samples. These results suggest that studies of biometric discrimination using MovAlyzeR® , specifically those based on the spatial-geometric feature set, support the validity of biometric matching algorithms based on FLASH ID® output.

Characterization and differentiation of aluminum powders used in improvised explosive devices. Part 2: Micromorphometric method refinement and preliminary statistical analysis.

Aluminum (Al) powder is commonly encountered in improvised explosive devices (IEDs) as a metallic fuel due to its availability and low cost. Although available commercially in powder form, amateur bomb-makers also produce their own Al powder via simple methods found online. In order to provide investigative leads and forensic intelligence, it is important to evaluate not only the composition of homemade devices, but also to distinguish between the various forms of Al powder they contain. To achieve this goal, a method using automated microscopy in combination with statistical techniques has been demonstrated to have the potential to provide source discrimination and investigative leads in source attribution of Al powders in IEDs. The present research refined this method and investigated 59 industrially and amateurly produced Al powder sources with seven subsamples per source using two traditional linear discriminant analyses (LDA), one with a standard data split for training and testing, and another using leave-one-out cross-validation. Averaging the classification accuracies for the two LDA-based analyses, LDA has the ability to correctly classify 59.26%, 83.35%, and 80.69% of the samples based on their powder source, type, and production method, respectively. This classification accuracy represents a 3407%, 317%, and 61.38% increase in accuracy from random class assignment, respectively. Further, in most instances of incorrect data attribution to a particular source, the subsample has been misidentified with another sample of the same powder type or production method.

Characterization and differentiation of aluminum powders used in improvised explosive devices - Part 1: Proof of concept of the utility of particle micromorphometry.

Aluminum (Al) powders are commonly used in improvised explosive devices as metallic fuels, a component of explosive mixtures. These powders can be obtained readily from industrial-scale and consumer products, and produced using unsophisticated "kitchen chemistry" techniques. This research demonstrates the potential of automated particle micromorphometry for comparisons between known source and questioned Al powders recovered from IEDs, as well as for insight into the method of Al powder manufacture. Al powder samples were obtained from legitimate manufacturers, and 56 samples were produced "in-house" from Al-containing spray paints and ball-milled Al foils. Transmitted light microscope images of Al powder particles were acquired using an automated stage with automated z-focus; 17 size and shape parameters were measured for all particles. Approximately 37,000-2,500,000 particles/sample were analyzed using an open-source statistical package with customized code. Dimensionality reduction was required for processing the large datasets: eight of the 17 measured variables were selected based on inspection of the correlation matrix. Data from four subsamples from each of the 56 samples produced using "in-house" methods were analyzed using ANOVA to assess the within- and between-sample variation. High within-sample variation was noted; however, ANOVA and post-hoc Tukey's honestly significant difference (HSD) tests demonstrated that the between-sample variation was substantially larger than the within-sample variation. Each sample could be differentiated from all other samples in the test set. Future experiments will focus on ways to reduce the within-sample variation, and additional statistical and microanalytical methods to classify sources and confidently constrain the method of Al powder manufacture.

Anterior cruciate ligament intactness in osteoarthritic patients indicated for total knee arthroplasty: a systematic literature review and meta-analysis.

Bi-cruciate retaining total knee arthroplasty (BCR TKA) is thought to result in more natural knee kinematics compared to conventional TKA designs. This may lead to a reduction in dissatisfied patients after TKA. An intact anterior cruciate ligament (ACL) is a prerequisite for implantation of a BCR TKA but the frequency of an intact ACL in patients indicated for TKA is not well known. The objective of this systematic literature review was to determine the presence of an intact ACL in patients undergoing TKA by intraoperative macroscopic or MRI assessment. A systematic literature review was conducted using PubMed™ and EMBASE™ in June 2020. The ACL of patients with knee osteoarthritis (OA) undergoing TKA was classified as present (including intact and degenerated) vs. absent, and as intact vs. not fully intact. Proportional meta-analyses were performed. 2840 articles were identified and screened. 135 full texts were analyzed and 18 studies met the inclusion criteria for subsequent qualitative and quantitative meta-analysis. Analysis of the status of the ACL when assessed intraoperatively during TKA showed that the ligament was present in 79.4% of patients (CI: 73.5-84.3%), from 14 studies with 2067 cases studied. The ACL was determined to be intact in 55.0% of patients (CI: 45.3-64.4%), from 14 studies with 1916 cases. Preoperative ACL assessment using MRI (2 studies) revealed it was present in 82.9% of 193 cases (CI: 76.9-87.6%), and intact in 56.8% of 176 cases (CI: 8.2-94.7%). This systematic literature review shows that the ACL is macroscopically intact in more than half of patients with knee OA undergoing TKA, based on intraoperative assessment of the ligament. The results suggest BCR TKA may be considered as an alternative to traditional TKA in a large number of TKA patients. More high-quality studies are needed to better understand the functional status of the ACL in TKA patients.Level of evidence III.

Use of an Automated System to Evaluate Feature Dissimilarities in Handwriting Under a Two-Stage Evaluative Process*, †.

The two-stage evaluative process is an established framework utilized by forensic document examiners (FDEs) for reaching a conclusion about the source(s) of handwritten evidence. In the second, or discrimination, stage, the examiner attempts to estimate the rarity of observations in a relevant background population. Unfortunately, control samples from a relevant background population are often unavailable, leaving the FDE to reach this determination based on subjective experience. Automated handwriting feature recognition systems are capable of performing both feature comparison and discrimination, yet these systems have not been subjected to empirical validation studies. In the present study, we repurposed a commercially available automated system to generate empirical distributions for ranking feature dissimilarity scores among pairs of handwritten phrases. The blinded results of this automated process were used to survey an international cohort of 36 FDEs regarding their strength of support for same- and different-writer propositions. The survey served to cross-validate FDE decision-making under the two-stage approach. Results from the survey demonstrated a clear pattern of response consistent with ground truth. Predictive regression analyses indicated that the automated feature dissimilarity scores and the log of their cumulative distribution functions accounted for 72% of the variability in FDE opinions. This study demonstrated that feature dissimilarity scores acquired using automated processes and their distributions are closely aligned with FDE decision-making processes supporting the heuristic value of the two-stage evaluative framework.

Strelka2: fast and accurate calling of germline and somatic variants.

We describe Strelka2 ( https://github.com/Illumina/strelka ), an open-source small-variant-calling method for research and clinical germline and somatic sequencing applications. Strelka2 introduces a novel mixture-model-based estimation of insertion/deletion error parameters from each sample, an efficient tiered haplotype-modeling strategy, and a normal sample contamination model to improve liquid tumor analysis. For both germline and somatic calling, Strelka2 substantially outperformed the current leading tools in terms of both variant-calling accuracy and computing cost.

A Set of Handwriting Features for Use in Automated Writer Identification.

A writer's biometric identity can be characterized through the distribution of physical feature measurements ("writer's profile"); a graph-based system that facilitates the quantification of these features is described. To accomplish this quantification, handwriting is segmented into basic graphical forms ("graphemes"), which are "skeletonized" to yield the graphical topology of the handwritten segment. The graph-based matching algorithm compares the graphemes first by their graphical topology and then by their geometric features. Graphs derived from known writers can be compared against graphs extracted from unknown writings. The process is computationally intensive and relies heavily upon statistical pattern recognition algorithms. This article focuses on the quantification of these physical features and the construction of the associated pattern recognition methods for using the features to discriminate among writers. The graph-based system described in this article has been implemented in a highly accurate and approximately language-independent biometric recognition system of writers of cursive documents.

An argument against presenting interval quantifications as a surrogate for the value of evidence.

In the various forensic science disciplines, recent analytical developments paired with modern statistical computational tools have led to the proliferation of adhoc techniques for quantifying the probative value of forensic evidence. Many legal and scientific scholars agree that the value of evidence should be reported as a likelihood ratio or a Bayes Factor. Quantifying the probative value of forensic evidence is subjected to many sources of variability and uncertainty. There is currently a debate on how to characterize the reliability of the value of evidence. Some authors have proposed associating a confidence/credible interval with the value of evidence assigned to a collection of forensic evidence. In this paper, we will discuss the reasons for our opinion that interval quantifications for the value of evidence should not be used directly in the Bayesian decision-making process to determine the support of the evidence for one of the two competing hypotheses.

Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications.

UNLABELLED: : We describe Manta, a method to discover structural variants and indels from next generation sequencing data. Manta is optimized for rapid germline and somatic analysis, calling structural variants, medium-sized indels and large insertions on standard compute hardware in less than a tenth of the time that comparable methods require to identify only subsets of these variant types: for example NA12878 at 50× genomic coverage is analyzed in less than 20 min. Manta can discover and score variants based on supporting paired and split-read evidence, with scoring models optimized for germline analysis of diploid individuals and somatic analysis of tumor-normal sample pairs. Call quality is similar to or better than comparable methods, as determined by pedigree consistency of germline calls and comparison of somatic calls to COSMIC database variants. Manta consistently assembles a higher fraction of its calls to base-pair resolution, allowing for improved downstream annotation and analysis of clinical significance. We provide Manta as a community resource to facilitate practical and routine structural variant analysis in clinical and research sequencing scenarios. AVAILABILITY AND IMPLEMENTATION: Manta is released under the open-source GPLv3 license. Source code, documentation and Linux binaries are available from https://github.com/Illumina/manta. CONTACT: csaunders@illumina.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.